Eivind Hovig

• Agudo, Maria Martin; Pol, Henk Van der; Stav, Gabriel Bratseth; Kringelbach, Tina; Puco, Katarina & Flobak, Åsmund [Vis alle 10 forfattere av denne artikkelen] (2026). ‘Crossing borders’ in data standardisation: application of OMOP CDM in an international clinical trial network in precision cancer medicine. Acta Oncologica. ISSN 0284-186X. 65, s. 163–163. doi: 10.2340/1651-226x.2026.45120. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Shadrin, Alexey; Frei, Oleksandr; Rahman, Mohammad Zillur; Akdeniz, Bayram Cevdet & Filiz, Tahir Tekin [Vis alle 29 forfattere av denne artikkelen] (2026). Family genetic designs in MoBa provide insights into health and functioning. Nature. ISSN 0028-0836. doi: 10.1038/s41586-026-10926-5. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies using large, population-based samples of unrelated individuals have discovered thousands of genetic associations with health and disease1. These studies can help explain genetic and environmental risks. However, increasing evidence suggests that population-based estimates, while precise, can also reflect confounding that affects their use and interpretation. This confounding can be overcome using data from genotyped family members, such as nuclear mother–father–child trios2,3. However, samples of genotyped families are rare4,5,6,7,8,9,10,11. Here we illustrate some of the advantages of familial data using the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based cohort of parents and offspring with extensive genotype data (n ≈ 230,000) (ref. 3), along with broad and longitudinal phenotyping of health and functioning. We provide an overview of MoBa and describe the quality control of genotype data tailored to this extensively related sample. We then use trio data to illustrate how family-based genomic designs can identify distinct direct and indirect sources of genetic influence and structural confounding. As examples, we analyse children’s height, educational achievement, depressive symptoms and sleep duration. These demonstrations highlight MoBa as a broadly valuable resource for advancing understanding of health and functioning across the lifecourse and generations.

• Nakken, Sigve; Edsjö, Anders; Lehtiö, Janne; Nygaard, Vigdis; Roepman, Paul & Rosenquist, Richard [Vis alle 69 forfattere av denne artikkelen] (2026). Towards an ecosystem of clinical decision support tools for precision cancer medicine. NPJ precision oncology. doi: 10.1038/s41698-026-01551-6. Fulltekst i vitenarkiv Vis sammendrag

  Molecular tumor boards are supported by clinical decision support system (CDSS) tools for the interpretation of complex molecular data towards personalized treatments. Current CDSS tools are genomics-focused and characterized by tight couplings between data ingestion, guideline-based reasoning logic and curated knowledgebases. Next-generation CDSS solutions should integrate multimodal data and learn from outcomes in an interoperable ecosystem, leveraging explainable, trustworthy output from AI models through rigorous clinical validation processes.

• Nygaard, Vigdis; Zhao, S.; Tamborero, D.; Rosenquist, R.; Stenzinger, A. & Roepman, P. [Vis alle 23 forfattere av denne artikkelen] (2026). Assessing clinical decision support system tools in precision oncology: piloting ring testing. ESMO Real World Data and Digital Oncology. 13. doi: 10.1016/j.esmorw.2026.100731. Fulltekst i vitenarkiv
• Abdallah, Majd; Nakken, Sigve; Georges, Mikaël; Bierkens, Mariska; Galvis, Johanna & Groppi, Alexis [Vis alle 15 forfattere av denne artikkelen] (2026). TrialMatchAI: an end-to-end AI-powered clinical trial recommendation system to streamline patient-to-trial matching. Nature Communications. 17(1). doi: 10.1038/s41467-026-70509-w. Fulltekst i vitenarkiv Vis sammendrag

  Patient recruitment remains a major bottleneck in clinical trials, calling for scalable and automated solutions. We present TrialMatchAI, an AI-powered recommendation system that automates patient-to-trial matching by processing heterogeneous clinical data, including structured records and unstructured physician notes. Built on fine-tuned, open-source large language models (LLMs) within a retrieval-augmented generation framework, TrialMatchAI ensures transparency and reproducibility and maintains a lightweight deployment footprint suitable for clinical environments. The system normalizes biomedical entities, retrieves relevant trials using a hybrid search strategy combining lexical and semantic similarity, re-ranks results, and performs criterion-level eligibility assessments using medical Chain-of-Thought reasoning. This pipeline delivers explainable outputs with traceable decision rationales. In real-world validation, 92% of oncology patients had at least one relevant trial retrieved within the top 20 recommendations. Evaluation across synthetic and real clinical datasets confirmed state-of-the-art performance, with expert assessment validating over 90% accuracy in criterion-level eligibility classification - particularly excelling in biomarker-driven matches. Designed for modularity and privacy, TrialMatchAI supports Phenopackets-standardized data, enables secure local deployment, and allows seamless replacement of LLM components as more advanced models emerge. By enhancing efficiency, interpretability and offering lightweight, open-source deployment, TrialMatchAI provides a scalable solution for AI-driven clinical trial matching in precision medicine.

• Hogstrom, Larson; Laurinavicius, Arvydas; Alvarez, Miguel Giraldez; Nakken, Sigve; Guldvik, Ingrid Jenny & Sanchez, Carlos Miguez [Vis alle 13 forfattere av denne artikkelen] (2026). European cancer data sharing: Analyses of an international survey. International Journal of Medical Informatics. ISSN 1386-5056. 218. doi: 10.1016/j.ijmedinf.2026.106544. Fulltekst i vitenarkiv
• Bos-Haugen, Steffan Daniel; Lund, Sigrún Helga; Fortner, Shannon Renee Turzanski; Hovig, Eivind & Langseth, Hilde (2026). Proteomic Profiling Using a Proximity Extension Assay Panel on Serum Samples Stored at −25°C Over Several Decades. Proteomics. ISSN 1615-9853. doi: 10.1002/pmic.70145. Fulltekst i vitenarkiv
• Ekstrøm, Per Olaf; Nakken, Sigve & Hovig, Eivind (2026). Exploring Taq polymerase induced mutations in part of BRAF exon 15 by sequencing and mutation enrichment. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. ISSN 0027-5107. 832. doi: 10.1016/j.mrfmmm.2026.111934. Fulltekst i vitenarkiv
• Pol, Henk van der; Kringelbach, Tina; Fagereng, Gro Live; Stav, Gabriel Bratseth; Agudo, Maria Martin & Mohammad, Soemeya Fooziye Haj [Vis alle 20 forfattere av denne artikkelen] (2025). Procedure for pooling clinical outcome data from DRUP-like clinical trials using the OMOP model. Journal of Clinical Oncology. ISSN 0732-183X. 43, s. e23165–e23165. doi: 10.1200/JCO.2025.43.16_suppl.e23165. Fulltekst i vitenarkiv
• Royo, Romina; Garcia, Eva; Schlunder, Irene; Hilmarsen, Anna Christina Wikstrøm; Thomsen, Mette Kielsholm & Cauet, Emilie [Vis alle 17 forfattere av denne artikkelen] (2025). Genomic data sharing in research across Europe: legal challenges and upcoming opportunities within the European Health Data Space. European Journal of Public Health. ISSN 1101-1262. 35, s. iii25–iii31. doi: 10.1093/eurpub/ckaf070. Fulltekst i vitenarkiv
• Møller, Pål; Ahadova, Aysel; Kloor, Matthias; Seppälä, Toni T.; Burn, John & Haupt, Saskia [Vis alle 18 forfattere av denne artikkelen] (2025). Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences. Hereditary Cancer in Clinical Practice. ISSN 1731-2302. 23. doi: 10.1186/s13053-025-00305-y. Fulltekst i vitenarkiv Vis sammendrag

  Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC ( path_APC ) and pathogenic mismatch repair gene ( path_MMR ) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage.

• Mattavelli, D.; Compagnoni, M.; Calza, S.; Ravanelli, M.; Plana, M. & Wichmann, G. [Vis alle 24 forfattere av denne artikkelen] (2025). A multiomic framework for predicting laryngo-esophageal dysfunction following induction chemotherapy in hypopharyngeal-laryngeal carcinoma. ESMO Open. 11(1), s. 105933–105933. doi: 10.1016/j.esmoop.2025.105933. Fulltekst i vitenarkiv
• Bope, Christian Domilongo; Kalyanasundaram, Sumana; Rand, Knut Dagestad; Nakken, Sigve; Lingjærde, Ole Christian & Hovig, Eivind (2025). StarSignDNA: Mutation-to-signature attribution for accurate representation of mutational processes in low-mutation contexts. NAR Genomics and Bioinformatics. 7(4). doi: 10.1093/nargab/lqaf181. Fulltekst i vitenarkiv Vis sammendrag

  All cell lineages accumulate mutations over time, increasing the probability that some lineages eventually become malignant. Many of the processes responsible for generating mutations leave a characteristic footprint in the genome that allows their presence to be detected. However, the mutational pattern in a tumour is usually the combined result of multiple mutational processes being at work simultaneously, and the problem of disentangling the different footprints and their relative impact then becomes a deconvolution problem. Several algorithms have been developed for this purpose, most of them involving a factorisation of the mutation count matrix into two non-negative matrices, representing, respectively, the underlying mutational signatures and the relative exposure to these signatures. Here, we introduce the StarSignDNA algorithm for mutational signature analysis, which offers efficient re-fitting and de novo mutational signature extraction. StarSignDNA performs mutation-to-signature attribution, assigning each mutation to its most probable causative mutational signature(s) based on the mutation’s trinucleotide context and the signature profiles. StarSignDNA demonstrates robust and clinically relevant performance in low-mutation contexts, with particular strengths in re-fitting analysis and balanced performance in de novo signature discovery. The package offers a command-line-based interface and data visualisation routines. The package is available at https://github.com/uio-bmi/StarSignDNA and can be installed via PyPI.

• Baydar, Damla Övek; Rauluseviciute, Ieva; Aronsen, Dina Ruud; Blanc-Mathieu, Romain; Bonthuis, Ine & de Beukelaer, Herman [Vis alle 34 forfattere av denne artikkelen] (2025). JASPAR 2026: expansion of transcription factor binding profiles and integration of deep learning models. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(D1), s. D184–D193. doi: 10.1093/nar/gkaf1209. Fulltekst i vitenarkiv Vis sammendrag

  Abstract JASPAR (https://jaspar.elixir.no/) is an open-access database that has provided high-quality, manually curated, and non-redundant DNA binding profiles for transcription factors (TFs) as position frequency matrices (PFMs) for over 20 years. We expanded the CORE (306 new profiles, 12% increase) and UNVALIDATED (433, 60% increase) collections with new PFMs and updated 13 existing profiles. We updated the TF binding site predictions and genome tracks for eight species. TF binding profile clusters and familial TF binding sites were updated accordingly. We integrate the inMOTIFin software to easily simulate regulatory sequences using JASPAR PFMs. To enrich TFs’ annotations, we provide scientific literature-based human TF target information. Notably, this release features a deep learning (DL) collection, providing a paradigm shift in modeling and characterizing TF–DNA interactions with 1259 BPNet models trained on Homo sapiens ENCODE chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets from 240 TFs and interpreted to reveal predictive motif patterns for the models. The motifs associated with the same TF were clustered to provide a summary of the binding properties, resulting in 240 primary and 113 alternative motif patterns in the DL collection. The JASPAR 2026 collections lay a foundation for future endeavors in genomic research, serving the scientific community in uncovering the mechanisms of gene regulation.

• Campos-Segura, Anthony Vladimir; Alvarez, Karin; Carrasco, Alexis German Murillo; Rossi, Benedito Mauro; Bohorquez, Mabel & Spirandelli, Florencia [Vis alle 77 forfattere av denne artikkelen] (2025). Characterization of Screening Strategies for Lynch Syndrome in Latin America. Clinical Gastroenterology and Hepatology. ISSN 1542-3565. 23(9), s. 1642–1654. doi: 10.1016/j.cgh.2024.12.026. Fulltekst i vitenarkiv Vis sammendrag

  Background & Aims In Latin America, genetic testing for Lynch syndrome (LS) has been partially implemented. Traditionally, LS diagnosis relied on the Amsterdam criteria and Bethesda guidelines, collectively known as traditional screening (TS). However, TS may miss up to 68% of LS cases. To improve detection rates, universal tumor screening (UTS) has been introduced. UTS involves screening all newly diagnosed patients with colorectal cancer for molecular markers to more effectively identify LS cases. Methods Clinical and molecular data on 1684 patients with colorectal cancer, collected between 1999 and 2020, were provided by 24 Latin American genetic cancer registries and centers. Germline genetic testing was not consistently performed across all cases. Results LS screening strategies were available for 72% (1209/1684) of cases, with germline testing conducted in one-quarter (304/1209) of these. Most cases (78%; n = 943) underwent UTS, primarily in Argentina, Chile, and Uruguay, whereas 22% (266/1209) were screened through TS. UTS identified deficient mismatch repair tumors in 29% (272/943) of cases. The rate of LS confirmed by sequencing was higher with UTS (53.3%; 65/122) compared with TS (47.8%; 87/182), although the difference was not statistically significant (P = .175). Conclusions UTS is widely implemented in Latin America; however, the low detection rate of LS demonstrated in this study raises concerns about the routine use of germline genetic testing in our region. Our study provides real-world outcomes that highlight disparities in screening uptake and counseling referrals, illustrating the challenges that Latin American countries face in hereditary cancer syndrome screening. These results contribute to the rationale for designing effective screening strategies for LS, which may also be applicable to other hereditary cancer syndromes, ultimately.

• Zhao, Sen; Nakken, Sigve; Vodak, Daniel & Hovig, Eivind (2025). FuSViz—visualization and interpretation of structural variation using cancer genomics and transcriptomics data. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(4). doi: 10.1093/nar/gkaf078. Fulltekst i vitenarkiv Vis sammendrag

  Structural variation (SV) is a frequent category of genetic alterations important for understanding cancer genome evolution and revealing key cancer driver events. With the development of high-throughput sequencing technologies, the ability to detect SVs of various sizes and types has improved, at both the DNA and RNA levels. However, SV calls are still prone to a considerable fraction of false positives, which necessitates visual inspection and manual curation as part of the quality control process. Identification of reliable and recurrent SVs in larger cohorts lends strength to revealing the driving roles of SVs in cancer development and to the discovery of potential diagnostic and prognostic biomarkers. Here, we present FuSViz, an application for visualization, interpretation, and prioritization of SVs. The tool provides multiple data view approaches in a user-friendly interface, allowing the investigation of prevalence and recurrence of SVs and relevant partner genes in a sample cohort. It integrates SV calls from DNA and RNA sequencing datasets to comprehensively illustrate the biological impact of SVs on the implicated genes and associated genomic regions. The functionality of FuSViz is intended for interrogation of both recurrent and private SVs, effectively assisting with pathogenicity evaluation and biomarker discovery in cancer sequencing projects.

• Zalevskaja, K.; Ojala, K.; Petrov, A.; Haupt, S.; Sunde, L. & Bernstein, I. [Vis alle 115 forfattere av denne artikkelen] (2025). Metachronous colorectal cancer risks after extended or segmental resection in MLH1, MSH2, and MSH6 Lynch syndrome: Multicentre study from the Prospective Lynch Syndrome Database. British Journal of Surgery. ISSN 0007-1323. 112(4). doi: 10.1093/bjs/znaf061. Fulltekst i vitenarkiv
• Padrik, Peeter; Tõnisson, Neeme; Hovda, Tone; Sahlberg, Guro Kristine Kleivi; Hovig, Eivind & Costa, Luís [Vis alle 21 forfattere av denne artikkelen] (2025). Guidance for the Clinical Use of the Breast Cancer Polygenic Risk Scores. Cancers. 17(7). doi: 10.3390/cancers17071056. Fulltekst i vitenarkiv
• Clarke, Alexander W.; Høye, Eirik; Hembrom, Anju Angelina; Paynter, Vanessa Molin; Vinther, Jakob & Wyrozemski, Lukasz [Vis alle 22 forfattere av denne artikkelen] (2025). MirGeneDB 3.0: Improved taxonomic sampling, uniform nomenclature of novel conserved microRNA families and updated covariance models. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(D1), s. D116–D128. doi: 10.1093/nar/gkae1094. Fulltekst i vitenarkiv
• Samarakoon, Pubudu Saneth; Fournous, Ghislain; Hansen, Lars Thomas; Wijesiri, Ashen; Zhao, Sen & A, Rodriguez Alex [Vis alle 12 forfattere av denne artikkelen] (2025). Benchmarking accelerated next-generation sequencing analysis pipelines. Bioinformatics Advances. 5(1), s. 1–13. doi: 10.1093/bioadv/vbaf085. Fulltekst i vitenarkiv Vis sammendrag

  Motivation Industry-standard central processing unit (CPU)-based next-generation sequencing (NGS) analysis tools have led to longer runtimes, affecting their utility in time-sensitive clinical practices and population-scale research studies. To address this, researchers have developed accelerated NGS platforms like DRAGEN and Parabricks, which have significantly reduced runtimes—from days to hours. However, these studies have evaluated accelerated platforms independently without sufficiently assessing computational resource usage or thoroughly investigating speedup scalability, a gap our study is designed to address. Results Corroborating previous studies, accelerated pipelines demonstrated shorter runtimes than CPU-only approaches, with Parabricks-H100 demonstrating the highest speedups, followed by DRAGEN. In mapping, DRAGEN outperformed Parabricks (L4 and A100) and matched H100 speedups. Parabricks (A100 and H100) variant calling demonstrated higher speedups than DRAGEN. Moreover, DRAGEN and Parabricks-H100 mapping showed positive trends in the coverage-based scalability analysis, while other configurations failed to scale effectively. Our profiler analysis provided new insights into the relationships between Parabricks’ performances and resource usage patterns, revealing its potential for further improvements. Our findings and cost comparison help researchers select accelerated platforms based on coverage needs, timeframes, and budget, while suggesting optimization strategies.

• Casali, P.G.; Antoine-Poirel, H.; Berrocoso, S.; Blay, J.-Y.; Dubois, T. & Ferrari, A. [Vis alle 19 forfattere av denne artikkelen] (2025). Health networking on cancer in the European Union: a ‘green paper’ by the EU Joint Action on Networks of Expertise (JANE). ESMO Open. 10(2). doi: 10.1016/j.esmoop.2024.104126. Fulltekst i vitenarkiv
• Reppe, Sjur; Gundersen, Sveinung; Sandve, Geir Kjetil Ferkingstad; Wang, Yunpeng; Andreassen, Ole A. & Medina-Gomez, Carolina [Vis alle 10 forfattere av denne artikkelen] (2024). Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 25(10). doi: 10.3390/ijms25105554. Fulltekst i vitenarkiv Vis sammendrag

  Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n=84) from clinically well-characterized postmenopausal women (50 to 86 years) using microchips and RNA sequencing. Thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and their biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying overlap in single nucleotide polymorphisms (SNPs) within several genes encoding the aBMD and CVD associated transcripts.The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

• Ivarsdottir, Erna V.; Gudmundsson, Julius; Tragante, Vinicius; Sveinbjornsson, Gardar; Kristmundsdottir, Snaedis & Stacey, Simon N. [Vis alle 58 forfattere av denne artikkelen] (2024). Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. Nature Genetics. ISSN 1061-4036. 56(11), s. 2422–2433. doi: https:/rdcu.be/dYuc6. Fulltekst i vitenarkiv
• Ellegaard, Martin Rene; Ebenesersdóttir, S. Sunna; Moore, Kristjan H.S.; Petersen, Anna Helena; Vågene, Åshild J. & Bieker, Vanessa Carina [Vis alle 20 forfattere av denne artikkelen] (2024). Corroborating written history with ancient DNA: The case of the Well-man described in an Old Norse saga. iScience. 27(11). doi: 10.1016/j.isci.2024.111076. Fulltekst i vitenarkiv Vis sammendrag

  The potential of ancient DNA analyses to provide independent sources of information about events in the historical record remains to be demonstrated. Here we apply palaeogenomic analysis to human remains excavated from a medieval well at the ruins of Sverresborg Castle in central Norway. In Sverris Saga, the Old Norse saga of King Sverre Sigurdsson, one passage details a 1197-CE raid on the castle and mentions a dead man thrown into the well. Radiocarbon dating supports that these are that individual’s remains. We sequenced the Well-man’s nuclear genome to 3.4× and compared it to Scandinavian populations, revealing he was closely related to inhabitants of southern Norway. This was surprising because King Sverre’s defeated army was assumed to be recruited from parts of central Norway, whereas the raiders were from the south. The findings also indicate that the unique genetic drift seen in present-day southern Norwegians already existed 800 years ago.

• Mattavelli, Davide; Wichmann, Gunnar; Smussi, Davide; Paderno, Alberto; Plana, Maria Serrahima & Mesia, Ricard Nin [Vis alle 21 forfattere av denne artikkelen] (2024). Is precision medicine the solution to improve organ preservation in laryngeal/hypopharyngeal cancer? A position paper by the Preserve Research Group. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1433333. Fulltekst i vitenarkiv
• Edsjö, Anders; Russnes, Hege Elisabeth Giercksky; Lehtiö, Janne; Tamborero, David; Hovig, Eivind & Stenzinger, Albrecht [Vis alle 65 forfattere av denne artikkelen] (2024). High-throughput molecular assays for inclusion in personalised oncology trials – State-of-the-art and beyond. Journal of Internal Medicine. ISSN 0954-6820. 295(6), s. 785–803. doi: 10.1111/joim.13785. Fulltekst i vitenarkiv Vis sammendrag

  In the last decades, the development of high-throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker-driven oncology trials. In this review, strengths and limitations of various state-of-the-art sequencing technologies, including gene panel sequencing (DNA and RNA), whole-exome/whole-genome sequencing and whole-transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial.

• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Shadrin, Alexey; Vetrov, Dmitry; Kropotov, Dmitry & Hovig, Eivind [Vis alle 8 forfattere av denne artikkelen] (2024). Finemap-MiXeR: A variational Bayesian approach for genetic finemapping. PLoS Genetics. ISSN 1553-7390. 20(8). doi: 10.1371/journal.pgen.1011372. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies (GWAS) implicate broad genomic loci containing clusters of highly correlated genetic variants. Finemapping techniques can select and prioritize variants within each GWAS locus which are more likely to have a functional influence on the trait. Here, we present a novel method, Finemap-MiXeR, for finemapping causal variants from GWAS summary statistics, controlling for correlation among variants due to linkage disequilibrium. Our method is based on a variational Bayesian approach and direct optimization of the Evidence Lower Bound (ELBO) of the likelihood function derived from the MiXeR model. After obtaining the analytical expression for ELBO’s gradient, we apply Adaptive Moment Estimation (ADAM) algorithm for optimization, allowing us to obtain the posterior causal probability of each variant. Using these posterior causal probabilities, we validated Finemap-MiXeR across a wide range of scenarios using both synthetic data, and real data on height from the UK Biobank. Comparison of Finemap-MiXeR with two existing methods, FINEMAP and SuSiE RSS, demonstrated similar or improved accuracy. Furthermore, our method is computationally efficient in several aspects. For example, unlike many other methods in the literature, its computational complexity does not increase with the number of true causal variants in a locus and it does not require any matrix inversion operation. The mathematical framework of Finemap-MiXeR is flexible and may also be applied to other problems including cross-trait and cross-ancestry finemapping.

• Møller, Pål; Haupt, Saskia; Ahadova, Aysel; Kloor, Matthias; Sampson, Julian R. & Sunde, Lone [Vis alle 29 forfattere av denne artikkelen] (2024). Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated “Big Bang” pathway to CRC in three of the four Lynch syndromes. Hereditary Cancer in Clinical Practice. ISSN 1731-2302. 22(1). doi: 10.1186/s13053-024-00279-3. Fulltekst i vitenarkiv Vis sammendrag

  Background Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. Materials and methods We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. Results Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. Conclusions Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

• Fossen, Erlend Ignacio Fleck; Moreira-Soares, Maurício; Leblanc, Marissa Erin; Frigessi, Arnoldo; Hovig, Eivind & Lopez-Perez, Laura [Vis alle 20 forfattere av denne artikkelen] (2024). External validation of prognostic and predictive gene signatures in head and neck cancer patients. medRxiv. doi: 10.1101/2024.09.24.24314278. Fulltekst i vitenarkiv
• Akdeniz, Bayram Cevdet; Morris, Andrew Hayden; Møller, Pål; Andreassen, Ole A.; Hovig, Eivind & Valentin, Mev Dominguez (2024). Evaluation of a combined model of Polygenic Risk Score and mismatch repair genes in the association of colorectal cancer for Norwegian cohort. Tumori (Milano). ISSN 0300-8916. doi: 10.1177/03008916241303648. Fulltekst i vitenarkiv
• Bai, Baoyan; Wise, Jillian Frances; Vodak, Daniel; Nakken, Sigve; Sharma, Ankush & Blaker, Yngvild Nuvin [Vis alle 23 forfattere av denne artikkelen] (2024). Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma. Blood Cancer Journal. 14:147(1), s. 1–12. doi: 10.1038/s41408-024-01124-5. Fulltekst i vitenarkiv Vis sammendrag

  Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.

• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Hagen, Espen; Filiz, Tahir Tekin; Karthikeyan, Sandeep & Pasman, Joëlle [Vis alle 18 forfattere av denne artikkelen] (2024). COSGAP: COntainerized Statistical Genetics Analysis Pipelines. Bioinformatics Advances. 4(1). doi: 10.1093/bioadv/vbae067. Fulltekst i vitenarkiv Vis sammendrag

  The collection and analysis of sensitive data in large-scale consortia for statistical genetics is hampered by multiple challenges, due to their non-shareable nature. Time-consuming issues in installing software frequently arise due to different operating systems, software dependencies, and limited internet access. For federated analysis across sites, it can be challenging to resolve different problems, including format requirements, data wrangling, setting up analysis on high-performance computing (HPC) facilities, etc. Easier, more standardized, automated protocols and pipelines can be solutions to overcome these issues. We have developed one such solution for statistical genetic data analysis using software container technologies. This solution, named COSGAP: “COntainerized Statistical Genetics Analysis Pipelines,” consists of already established software tools placed into Singularity containers, alongside corresponding code and instructions on how to perform statistical genetic analyses, such as genome-wide association studies, polygenic scoring, LD score regression, Gaussian Mixture Models, and gene-set analysis. Using provided helper scripts written in Python, users can obtain auto-generated scripts to conduct the desired analysis either on HPC facilities or on a personal computer. COSGAP is actively being applied by users from different countries and projects to conduct genetic data analyses without spending much effort on software installation, converting data formats, and other technical requirements.

• Rauluseviciute, Ieva; Riudavets-Puig, Rafael; Blanc-Mathieu, Romain; Mondragon, Jaime Abraham Castro; Ferenc, Katalin Terezia & Kumar, Vipin [Vis alle 20 forfattere av denne artikkelen] (2023). JASPAR 2024: 20th anniversary of the open-access database of transcription factor binding profiles. Nucleic Acids Research (NAR). ISSN 0305-1048. 52(D1), s. D174–D182. doi: 10.1093/nar/gkad1059. Fulltekst i vitenarkiv Vis sammendrag

  JASPAR (https://jaspar.elixir.no/) is a widely-used open-access database presenting manually curated high-quality and non-redundant DNA-binding profiles for transcription factors (TFs) across taxa. In this 10th release and 20th-anniversary update, the CORE collection has expanded with 329 new profiles. We updated three existing profiles and provided orthogonal support for 72 profiles from the previous release's UNVALIDATED collection. Altogether, the JASPAR 2024 update provides a 20% increase in CORE profiles from the previous release. A trimming algorithm enhanced profiles by removing low information content flanking base pairs, which were likely uninformative (within the capacity of the PFM models) for TFBS predictions and modelling TF-DNA interactions. This release includes enhanced metadata, featuring a refined classification for plant TFs’ structural DNA-binding domains. The new JASPAR collections prompt updates to the genomic tracks of predicted TF binding sites (TFBSs) in 8 organisms, with human and mouse tracks available as native tracks in the UCSC Genome browser. All data are available through the JASPAR web interface and programmatically through its API and the updated Bioconductor and pyJASPAR packages. Finally, a new TFBS extraction tool enables users to retrieve predicted JASPAR TFBSs intersecting their genomic regions of interest.

• Akdeniz, Bayram Cevdet; Mattingsdal, Morten; Dominguez-Valentin, Mev; Frei, Oleksandr; Shadrin, Alexey & Puustusmaa, Mikk [Vis alle 12 forfattere av denne artikkelen] (2023). A Breast Cancer Polygenic Risk Score Is Feasible for Risk Stratification in the Norwegian Population. Cancers. 15(16). doi: 10.3390/cancers15164124. Fulltekst i vitenarkiv Vis sammendrag

  Background: Statistical associations of numerous single nucleotide polymorphisms with breast cancer (BC) have been identified in genome-wide association studies (GWAS). Recent evidence suggests that a Polygenic Risk Score (PRS) can be a useful risk stratification instrument for a BC screening strategy, and a PRS test has been developed for clinical use. The performance of the PRS is yet unknown in the Norwegian population. Aim: To evaluate the performance of PRS models for BC in a Norwegian dataset. Methods: We investigated a sample of 1053 BC cases and 7094 controls from different regions of Norway. PRS values were calculated using four PRS models, and their performance was evaluated by the area under the curve (AUC) and the odds ratio (OR). The effect of the PRS on the age of onset of BC was determined by a Cox regression model, and the lifetime absolute risk of developing BC was calculated using the iCare tool. Results: The best performing PRS model included 3820 SNPs, which yielded an AUC = 0.625 and an OR = 1.567 per one standard deviation increase. The PRS values of the samples correlate with an increased risk of BC, with a hazard ratio of 1.494 per one standard deviation increase (95% confidence interval of 1.406–1.588). The individuals in the highest decile of the PRS have at least twice the risk of developing BC compared to the individuals with a median PRS. The results in this study with Norwegian samples are coherent with the findings in the study conducted using Estonian and UK Biobank samples. Conclusion: The previously validated PRS models have a similar observed accuracy in the Norwegian data as in the UK and Estonian populations. A PRS provides a meaningful association with the age of onset of BC and lifetime risk. Therefore, as suggested in Estonia, a PRS may also be integrated into the screening strategy for BC in Norway.

• Nakken, Sigve; Gundersen, Sveinung; Bernal, Fabian Leonardo Martinez; Polychronopoulos, Dimitris; Hovig, Eivind & Wesche, Jørgen (2023). Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR. International Journal of Cancer. ISSN 0020-7136. 153(10), s. 1819–1828. doi: 10.1002/ijc.34666. Fulltekst i vitenarkiv Vis sammendrag

  Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform (https://oncotools.elixir.no), and can also be accessed as a stand-alone R package (https://github.com/sigven/oncoEnrichR).

• Kalyanasundaram, Sumana; Lefol, Yohan Pierre; Gundersen, Sveinung; Rognes, Torbjørn; Alsøe, Lene & Nilsen, Hilde [Vis alle 9 forfattere av denne artikkelen] (2023). hGSuite HyperBrowser: A web-based toolkit for hierarchical metadata-informed analysis of genomic tracks. PLOS ONE. 18(7). doi: 10.1371/journal.pone.0286330. Fulltekst i vitenarkiv Vis sammendrag

  Many high-throughput sequencing datasets can be represented as objects with coordinates along a reference genome. Currently, biological investigations often involve a large number of such datasets, for example representing different cell types or epigenetic factors. Drawing overall conclusions from a large collection of results for individual datasets may be challenging and time-consuming. Meaningful interpretation often requires the results to be aggregated according to metadata that represents biological characteristics of interest. In this light, we here propose the hierarchical Genomic Suite HyperBrowser (hGSuite), an open-source extension to the GSuite HyperBrowser platform, which aims to provide a means for extracting key results from an aggregated collection of high-throughput DNA sequencing data. The hGSuite utilizes a metadata-informed data cube to calculate various statistics across the multiple dimensions of the datasets. With this work, we show that the hGSuite and its associated data cube methodology offers a quick and accessible way for exploratory analysis of large genomic datasets. The web-based toolkit named hGsuite Hyperbrowser is available at https://hyperbrowser.uio.no/hgsuite under a GPLv3 license.

• Billingham, Lucinda; Brown, Lynn; Framke, Theodor; Greystoke, Alistair; Hovig, Eivind & Mathur, Siddharta [Vis alle 13 forfattere av denne artikkelen] (2023). Histology independent drug development – Is this the future for cancer drugs? Cancer Treatment Reviews. ISSN 0305-7372. 123. doi: 10.1016/j.ctrv.2023.102674. Fulltekst i vitenarkiv
• Dominguez-Valentin, Mev; Haupt, Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone & Bernstein, Inge [Vis alle 116 forfattere av denne artikkelen] (2023). Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database. EClinicalMedicine. 58. doi: 10.1016/j.eclinm.2023.101909. Fulltekst i vitenarkiv
• Rodriguez-Varela, Ricardo; Moore, Kristjan H.S.; Ebenesersdottir, Sunna; Kilinc, Gulsah; Kjellström, Anna & Papmehl-Dufay, Ludvig [Vis alle 44 forfattere av denne artikkelen] (2023). The genetic history of Scandinavia from the Roman Iron Age to the present. Cell. ISSN 0092-8674. 186(1), s. 32–46. doi: 10.1016/j.cell.2022.11.024. Fulltekst i vitenarkiv Vis sammendrag

  We investigate a 2,000-year genetic transect through Scandinavia spanning the Iron Age to the present, based on 48 new and 249 published ancient genomes and genotypes from 16,638 modern individuals. We find regional variation in the timing and magnitude of gene flow from three sources: the eastern Baltic, the British-Irish Isles, and southern Europe. British-Irish ancestry was widespread in Scandinavia from the Viking period, whereas eastern Baltic ancestry is more localized to Gotland and central Sweden. In some regions, a drop in current levels of external ancestry suggests that ancient immigrants contributed proportionately less to the modern Scandinavian gene pool than indicated by the ancestry of genomes from the Viking and Medieval periods. Finally, we show that a north-south genetic cline that characterizes modern Scandinavians is mainly due to the differential levels of Uralic ancestry and that this cline existed in the Viking Age and possibly earlier.

• Høye, Eirik; Dagenborg, Vegar Johansen; Kristensen, Annette Torgunrud; Lund-Andersen, Christin; Fretland, Åsmund Avdem & Lorenz, Susanne [Vis alle 13 forfattere av denne artikkelen] (2023). T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases. GigaScience. 12. doi: 10.1093/gigascience/giad032. Fulltekst i vitenarkiv Vis sammendrag

  Background - Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite-stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumor-infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T-cell infiltration in CLM using T-cell receptor (TCR) repertoire sequencing. Eighty-five resected CLMs from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T-cell fractions were calculated, repertoire clonality was analyzed based on Hill evenness curves, and TCR sequence convergence was assessed using network analysis.<p> <p>Results - Increased T-cell fractions (10.6% vs. 6.3%) were detected in CLMs exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT-exposed tumors independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence.<p> <p>Conclusions - TCR repertoire sequencing can be used to quantify T-cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T-cell clonal expansion in CLM in a clinical context.

• Namløs, Heidi Maria; Khelik, Ksenia; Nakken, Sigve; Vodak, Daniel; Hovig, Eivind & Myklebost, Ola [Vis alle 8 forfattere av denne artikkelen] (2023). Chromosomal instability and a deregulated cell cycle are intrinsic features of high-risk gastrointestinal stromal tumours with a metastatic potential. Molecular Oncology. ISSN 1574-7891. 17(11), s. 2432–2450. doi: 10.1002/1878-0261.13514. Fulltekst i vitenarkiv Vis sammendrag

  Patients with localised, high-risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within 3 years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype. Using a multi-omics approach, we analysed a cohort of primary tumours from patients with untreated, resectable high-risk GISTs. We compared patients who developed metastatic disease within 3 years after finishing adjuvant imatinib treatment and patients without disease relapse after more than 5 years of follow-up. Combining genomics and transcriptomics data, we identified somatic mutations and deregulated mRNA and miRNA genes intrinsic to each group. Our study shows that increased chromosomal instability (CIN), including chromothripsis and deregulated kinetochore and cell cycle signalling, separates high-risk samples according to metastatic potential. The increased CIN seems to be an intrinsic feature for tumours that metastasise and should be further validated as a novel prognostic biomarker for high-risk GIST.

• Møller, Pål; Seppälä, Toni T.; Ahadova, Aysel; Crosbie, Emma J.; Holinski-Feder, Elke & Scott, Rodney [Vis alle 49 forfattere av denne artikkelen] (2023). Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement. Hereditary Cancer in Clinical Practice. ISSN 1731-2302. 21(1), s. 1–12. doi: 10.1186/s13053-023-00263-3. Fulltekst i vitenarkiv Vis sammendrag

  The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

• Fromm, Bastian; Høye, Eirik; Domanska, Diana; Zhong, Xiangfu; Aparicio-Puerta, Ernesto & Ovchinnikov, Vladimir [Vis alle 18 forfattere av denne artikkelen] (2022). MirGeneDB 2.1: toward a complete sampling of all major animal phyla. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(D1), s. D204–D210. doi: 10.1093/nar/gkab1101. Fulltekst i vitenarkiv Vis sammendrag

  We describe an update of MirGeneDB, the manually curated microRNA gene database. Adhering to uniform and consistent criteria for microRNA annotation and nomenclature, we substantially expanded MirGeneDB with 30 additional species representing previously missing metazoan phyla such as sponges, jellyfish, rotifers and flatworms. MirGeneDB 2.1 now consists of 75 species spanning over ∼800 million years of animal evolution, and contains a total number of 16 670 microRNAs from 1549 families. Over 6000 microRNAs were added in this update using ∼550 datasets with ∼7.5 billion sequencing reads. By adding new phylogenetically important species, especially those relevant for the study of whole genome duplication events, and through updating evolutionary nodes of origin for many families and genes, we were able to substantially refine our nomenclature system. All changes are traceable in the specifically developed MirGeneDB version tracker. The performance of read-pages is improved and microRNA expression matrices for all tissues and species are now also downloadable. Altogether, this update represents a significant step toward a complete sampling of all major metazoan phyla, and a widely needed foundation for comparative microRNA genomics and transcriptomics studies. MirGeneDB 2.1 is part of RNAcentral and Elixir Norway, publicly and freely available at http://www.mirgenedb.org/.

• Gopalakrishnan, Shyam; Ebenesersdottir, S.Sunna; Lundstrøm, Inge K.C.; Turner-Walker, Gordon; Moore, Kristjan H.S. & Luisi, Pierre [Vis alle 60 forfattere av denne artikkelen] (2022). The population genomic legacy of the second plague pandemic. Current Biology. ISSN 0960-9822. 32(21), s. 4743–4751. doi: 10.1016/j.cub.2022.09.023. Fulltekst i vitenarkiv Vis sammendrag

  Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.

• Ellingsen, Espen Basmo; Aamdal, Elin; Guren, Tormod Kyrre; Lilleby, Wolfgang; Brunsvig, Paal Fr. & Mangsbo, Sara M [Vis alle 11 forfattere av denne artikkelen] (2022). Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1: Long-Term follow-up of three phase i clinical trials. Journal for ImmunoTherapy of Cancer (JITC). 10(5), s. 1–13. doi: 10.1136/jitc-2021-004345. Fulltekst i vitenarkiv Vis sammendrag

  Background Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years. Methods 52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses. Results In total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen. Conclusion Long-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.

• Misund, Kristine; Bruinink, Davine Hofste op; Coward, Eivind; Hoogenboezem, Remco M.; Rustad, Even Holth & Sanders, Mathijs A. [Vis alle 16 forfattere av denne artikkelen] (2022). Clonal evolution after treatment pressure in multiple myeloma: heterogenous genomic aberrations and transcriptomic convergence. Leukemia. ISSN 0887-6924. 36(7), s. 1887–1897. doi: 10.1038/s41375-022-01597-y. Fulltekst i vitenarkiv Vis sammendrag

  We investigated genomic and transcriptomic changes in paired tumor samples of 29 in-house multiple myeloma (MM) patients and 28 patients from the MMRF CoMMpass study before and after treatment. A change in clonal composition was found in 46/57 (82%) of patients, and single-nucleotide variants (SNVs) increased from median 67 to 86. The highest increase in prevalence of genetic aberrations was found in RAS genes (60% to 72%), amp1q21 (18% to 35%), and TP53 (9% to 18%). The SBS-MM1 mutation signature was detected both in patients receiving high and low dose melphalan. A total of 2589 genes were differentially expressed between early and late samples (FDR < 0.05). Gene set enrichment analysis (GSEA) showed increased expression of E2F, MYC, and glycolysis pathways and a decreased expression in TNF-NFkB and TGFbeta pathways in late compared to early stage. Single sample GSEA (ssGSEA) scores of differentially expressed pathways revealed that these changes were most evident in end-stage disease. Increased expression of several potentially targetable genes was found at late disease stages, including cancer-testis antigens, XPO1 and ABC transporters. Our study demonstrates a transcriptomic convergence of pathways supporting increased proliferation and metabolism during disease progression in MM.

• Flobak, Åsmund; Skånland, Sigrid S; Hovig, Eivind; Tasken, Kjetil & Russnes, Hege Elisabeth Giercksky (2022). Functional precision cancer medicine: drug sensitivity screening enabled by cell culture models. TIPS - Trends in Pharmacological Sciences. ISSN 0165-6147. 43(11), s. 973–985. doi: 10.1016/j.tips.2022.08.009. Fulltekst i vitenarkiv Vis sammendrag

  Functional precision medicine is a new, emerging area that can guide cancer treatment by capturing information from direct perturbations of tumor-derived, living cells, such as by drug sensitivity screening. Precision cancer medicine as currently implemented in clinical practice has been driven by genomics, and current molecular tumor boards rely extensively on genomic characterization to advise on therapeutic interventions. However, genomic biomarkers can only guide treatment decisions for a fraction of the patients. In this review we provide an overview of the current state of functional precision medicine, highlight advances for drug-sensitivity screening enabled by cell culture models, and discuss how artificial intelligence (AI) can be coupled to functional precision medicine to guide patient stratification.

• Venizelos, Andreas; Engebrethsen, Christina; Deng, Wei; Geisler, Jürgen; Geisler, Stephanie & Iversen, Gjertrud Titlestad [Vis alle 18 forfattere av denne artikkelen] (2022). Clonal evolution in primary breast cancers under sequential epirubicin and docetaxel monotherapy. Genome Medicine. 14, s. 1–18. doi: 10.1186/s13073-022-01090-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Subclonal evolution during primary breast cancer treatment is largely unexplored. We aimed to assess the dynamic changes in subclonal composition of treatment-naïve breast cancers during neoadjuvant chemotherapy. Methods We performed whole exome sequencing of tumor biopsies collected before, at therapy switch, and after treatment with sequential epirubicin and docetaxel monotherapy in 51 out of 109 patients with primary breast cancer, who were included in a prospectively registered, neoadjuvant single-arm phase II trial. Results There was a profound and differential redistribution of subclones during epirubicin and docetaxel treatment, regardless of therapy response. While truncal mutations and main subclones persisted, smaller subclones frequently appeared or disappeared. Reassessment of raw data, beyond formal mutation calling, indicated that the majority of subclones seemingly appearing during treatment were in fact present in pretreatment breast cancers, below conventional detection limits. Likewise, subclones which seemingly disappeared were still present, below detection limits, in most cases where tumor tissue remained. Tumor mutational burden (TMB) dropped during neoadjuvant therapy, and copy number analysis demonstrated specific genomic regions to be systematically lost or gained for each of the two chemotherapeutics. Conclusions Sequential epirubicin and docetaxel monotherapy caused profound redistribution of smaller subclones in primary breast cancer, while early truncal mutations and major subclones generally persisted through treatment.

• Alver, Tine Norman; Heintz, Karen Marie; Hovig, Eivind & Bøe, Sigurd (2022). Cooperative induction of receptor tyrosine kinases contributes to adaptive MAPK drug resistance in melanoma through the PI3K pathway. Cancer Reports. doi: 10.1002/cnr2.1736. Fulltekst i vitenarkiv Vis sammendrag

  emurafenib-induced drug resistance in melanoma has been linked to receptor tyrosinekinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators ofmelanocyte and melanoma development. Here, we aimed to explore the complex mecha-nisms behind the MITF/SOX10-controlled RTK-induced drug resistance in melanoma. Toachieve this, we used a number of molecular techniques, including melanoma patient datafrom TCGA, vemurafenib-resistant melanoma cell lines, and knock-down studies. The mel-anoma cell lines were classified as proliferative or invasive based upon their MITF/AXLexpression activity. We measured the changeof expression activity for MITF/SOX10 andtheir receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved inRTK-induced drug resistance after vemurafenib treatment. We find that melanoma celllines characterized as proliferative (high MITF low AXL), transform into an invasive (lowMITF, high AXL) cell state after vemurafenibresistance, indicating novel feedback loopsand advanced compensatory regulation mechanisms between the master regulators,receptors, and ligands involved in vemurafenib-induced resistance. Together, our data dis-close fine-tuned mechanisms involved in RTK-facilitated vemurafenibresistance that willbe challenging to overcome by using single drug targeting strategies against melanoma.

• Hanes, Robert; Ayuda-Duran, Maria del Pilar; Rønneberg, Leiv; Nakken, Sigve; Hovig, Eivind & Zucknick, Manuela [Vis alle 7 forfattere av denne artikkelen] (2022). screenwerk: a modular tool for the design and analysis of drug combination screens. Bioinformatics. ISSN 1367-4803. 39(1). doi: 10.1093/bioinformatics/btac840. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Motivation There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data and generate data files that can be analyzed by synergy-finding bioinformatics applications. Results screenwerk is an open-source, end-to-end modular tool available as an R-package for the design and analysis of drug combination screens. The tool allows for a customized build of pipelines through its modularity and provides a flexible approach to quality control and data analysis. screenwerk is adaptable to various experimental requirements with an emphasis on precision medicine. It can be coupled to other R packages, such as bayesynergy, to identify synergistic and antagonistic drug interactions in cell lines or patient samples. screenwerk is scalable and provides a complete solution for setting up drug sensitivity screens, read raw measurements and consolidate different datasets, perform various types of quality control and analyze, report and visualize the results of drug sensitivity screens. Availability and implementation The R-package and technical documentation is available at https://github.com/Enserink-lab/screenwerk; the R source code is publicly available at https://github.com/Enserink-lab/screenwerk under GNU General Public License v3.0; bayesynergy is accessible at https://github.com/ocbe-uio/bayesynergy. Selected modules are available through Galaxy, an open-source platform for FAIR data analysis at https://oncotools.elixir.no Supplementary information Supplementary data are available at Bioinformatics online.

• Zavaleta, Elizabeth; Solis, Nelly; Palacios, Maria Isabel; Zevallos-Escobar, Liz Elva; Corales, Edison Vasquez & Bazo-Alvarez, Juan Carlos [Vis alle 17 forfattere av denne artikkelen] (2022). Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru. Cancers. 14(22), s. 1–13. doi: 10.3390/cancers14225603. Fulltekst i vitenarkiv Vis sammendrag

  Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T&gt;C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

• Ellingsen, Espen Basmo; Bounova, Gergana; Kerzeli, Iliana; Anzar, Irantzu; Simnica, Donjete & Aamdal, Elin [Vis alle 14 forfattere av denne artikkelen] (2022). Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination. Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03624-z. Fulltekst i vitenarkiv Vis sammendrag

  Background This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment. Methods The trial was an open-label, single-center phase I/IIa study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues. Results Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-γ gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-γ gene signature was detected in clinically responding patients. Conclusion Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors.

• Giliberto, Mariaserena; Santana, Leonardo Miranda; Holien, Toril; Misund, Kristine; Nakken, Sigve & Vodak, Daniel [Vis alle 12 forfattere av denne artikkelen] (2022). Mutational analysis and protein profiling predict drug sensitivity in multiple myeloma cell lines. Frontiers in Oncology. 12:1040730, s. 1–14. doi: 10.3389/fonc.2022.1040730. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Multiple myeloma (MM) is a heterogeneous disease where cancer-driver mutations and aberrant signaling may lead to disease progression and drug resistance. Drug responses vary greatly, and there is an unmet need for biomarkers that can guide precision cancer medicine in this disease. Methods: To identify potential predictors of drug sensitivity, we applied integrated data from drug sensitivity screening, mutational analysis and functional signaling pathway profiling in 9 cell line models of MM. We studied the sensitivity to 33 targeted drugs and their association with the mutational status of cancer-driver genes and activity level of signaling proteins. Results: We found that sensitivity to mitogen-activated protein kinase kinase 1 (MEK1) and phosphatidylinositol-3 kinase (PI3K) inhibitors correlated with mutations in NRAS/KRAS, and PI3K family genes, respectively. Phosphorylation status of MEK1 and protein kinase B (AKT) correlated with sensitivity to MEK and PI3K inhibition, respectively. In addition, we found that enhanced phosphorylation of proteins, including Tank-binding kinase 1 (TBK1), as well as high expression of B cell lymphoma 2 (Bcl-2), correlated with low sensitivity to MEK inhibitors. Discussion: Taken together, this study shows that mutational status and signaling protein profiling might be used in further studies to predict drug sensitivities and identify resistance markers in MM.

• Høye, Eirik; Fromm, Bastian; Böttger, Paul H.M.; Domanska, Diana; Kristensen, Annette Torgunrud & Lund-Andersen, Christin [Vis alle 13 forfattere av denne artikkelen] (2022). A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer. NAR Cancer. 4(1), s. 1–13. doi: 10.1093/narcan/zcab051. Fulltekst i vitenarkiv Vis sammendrag

  Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published nextgeneration sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as upregulated at multiple metastatic sites Mir-210 3p, Mir191 5p, Mir-8-P1b 3p [mir-141–3p], Mir-1307 5p and Mir-155 5p. Several have previously been implicated in metastasis through involvement in epithelial-tomesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

• Møller, Pål; Seppälä, Toni; Dowty, James G.; Haupt, Saskia; Dominguez-Valentin, Mev & Sunde, Lone [Vis alle 157 forfattere av denne artikkelen] (2022). Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium. Hereditary Cancer in Clinical Practice. ISSN 1731-2302. 20(1). doi: 10.1186/s13053-022-00241-1. Fulltekst i vitenarkiv Vis sammendrag

  Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Shadrin, Alexey; Vetrov, Dmitry; Kropotov, Dmitry & Dale, Anders [Vis alle 8 forfattere av denne artikkelen] (2022). Finemap-MiXeR: A variational Bayesian approach for genetic finemapping. BioRxiv. ISSN 0362-4331. Fulltekst i vitenarkiv
• Akdeniz, Bayram Cevdet; Frei, Oleksandr; Hagen, Espen; Filiz, Tahir Tekin; Karthikeyan, Sandeep & Pasman, Joëlle [Vis alle 18 forfattere av denne artikkelen] (2022). COGEDAP: A COmprehensive GEnomic Data Analysis Platform. arXiv.org. ISSN 2331-8422. Fulltekst i vitenarkiv
• Gundersen, Sveinung; Boddu, Sanjay; Capella-Gutierrez, Salvador; Drabløs, Finn; Fernández, José M. & Kompova, Radmila [Vis alle 10 forfattere av denne artikkelen] (2021). Recommendations for the FAIRification of genomic track metadata. F1000 Research. 10. doi: 10.12688/f1000research.28449.1. Fulltekst i vitenarkiv Vis sammendrag

  Background: Many types of data from genomic analyses can be represented as genomic tracks, i.e. features linked to the genomic coordinates of a reference genome. Examples of such data are epigenetic DNA methylation data, ChIP-seq peaks, germline or somatic DNA variants, as well as RNA-seq expression levels. Researchers often face difficulties in locating, accessing and combining relevant tracks from external sources, as well as locating the raw data, reducing the value of the generated information. Description of work: We propose to advance the application of FAIR data principles (Findable, Accessible, Interoperable, and Reusable) to produce searchable metadata for genomic tracks. Findability and Accessibility of metadata can then be ensured by a track search service that integrates globally identifiable metadata from various track hubs in the Track Hub Registry and other relevant repositories. Interoperability and Reusability need to be ensured by the specification and implementation of a basic set of recommendations for metadata. We have tested this concept by developing such a specification in a JSON Schema, called FAIRtracks, and have integrated it into a novel track search service, called TrackFind. We demonstrate practical usage by importing datasets through TrackFind into existing examples of relevant analytical tools for genomic tracks: EPICO and the GSuite HyperBrowser. Conclusion: We here provide a first iteration of a draft standard for genomic track metadata, as well as the accompanying software ecosystem. It can easily be adapted or extended to future needs of the research community regarding data, methods and tools, balancing the requirements of both data submitters and analytical end-users.

• Dominguez-Valentin, Mev; Plazzer, John-Paul; Sampson, Julian R.; Engel, Christoph; Aretz, Stefan & Jenkins, Mark A. [Vis alle 89 forfattere av denne artikkelen] (2021). No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study. Journal of Clinical Medicine. 10(13), s. 1–12. doi: 10.3390/jcm10132856. Fulltekst i vitenarkiv Vis sammendrag

  Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

• Aamdal, Elin; Inderberg, Else Marit; Ellingsen, Espen Basmo; Rasch, Wenche; Brunsvig, Paal Fr. & Aamdal, Steinar [Vis alle 13 forfattere av denne artikkelen] (2021). Combining a universal telomerase based cancer vaccine with ipilimumab in patients with metastatic melanoma - Five-year follow up of a phase I/IIa trial. Frontiers in Immunology. 12, s. 1–10. doi: 10.3389/fimmu.2021.663865. Fulltekst i vitenarkiv Vis sammendrag

  Background Ipilimumab improves survival for patients with metastatic malignant melanoma. Combining a therapeutic cancer vaccine with ipilimumab may increase efficacy by providing enhanced anti-tumor immune responses. UV1 consists of three synthetic long peptides from human telomerase reverse transcriptase (hTERT). These peptides comprise epitopes recognized by T cells from cancer patients experiencing long-term survival following treatment with a first-generation hTERT vaccine, and generate long-lasting immune responses in cancer patients when used as monotherapy. The objective of this trial was to investigate the safety and efficacy of combining UV1 with ipilimumab in metastatic melanoma. Patients and Methods In this phase I/IIa, single center trial [NCT02275416], patients with metastatic melanoma received repeated UV1 vaccinations, with GM-CSF as an adjuvant, in combination with ipilimumab. Patients were evaluated for safety, efficacy and immune response. Immune responses against vaccine peptides were monitored in peripheral blood by measuring antigen-specific proliferation and IFN-γ production. Results Twelve patients were recruited. Adverse events were mainly diarrhea, injection site reaction, pruritus, rash, nausea and fatigue. Ten patients showed a Th1 immune response to UV1 peptides, occurring early and after few vaccinations. Three patients obtained a partial response and one patient a complete response. Overall survival was 50% at 5 years. Conclusion Treatment was well tolerated. The rapid expansion of UV1-specific Th1 cells in the majority of patients indicates synergy between UV1 vaccine and CTLA-4 blockade. This may have translated into clinical benefit, encouraging the combination of UV1 vaccination with standard of care treatment regimes containing ipilimumab/CTLA-4 blocking antibodies.

• Ellingsen, Espen Basmo; Mangsbo, Sara; Hovig, Eivind & Gaudernack, Gustav (2021). Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential. Frontiers in Immunology. 12:682492, s. 1–15. doi: 10.3389/fimmu.2021.682492. Fulltekst i vitenarkiv Vis sammendrag

  Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.

• Seppälä, Toni T.; Dominguez-Valentin, Mev; Crosbie, Emma J.; Engel, Christoph; Aretz, Stefan & Macrae, Finlay [Vis alle 86 forfattere av denne artikkelen] (2021). Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report. European Journal of Cancer. ISSN 0959-8049. 148, s. 124–133. doi: 10.1016/j.ejca.2021.02.022. Fulltekst i vitenarkiv
• Pavlović, Milena; Scheffer, Lonneke; Motwani, Keshav; Kanduri, Chakravarthi; Kompova, Radmila & Vazov, Nikolay Aleksandrov [Vis alle 42 forfattere av denne artikkelen] (2021). The immuneML ecosystem for machine learning analysis of adaptive immune receptor repertoires. Nature Machine Intelligence. 3(11), s. 936–944. doi: 10.1038/s42256-021-00413-z. Fulltekst i vitenarkiv
• Nakken, Sigve; Lilleby, Wolfgang; Switlyk, Marta Daniela; Knudsen, Karen E.; Lilleby, Oscar & Zhao, Sen [Vis alle 10 forfattere av denne artikkelen] (2021). The quandary of dna-based treatment assessment in de novo metastatic prostate cancer in the era of precision oncology. Journal of Personalized Medicine. 11(5), s. 1–18. doi: 10.3390/jpm11050330. Fulltekst i vitenarkiv Vis sammendrag

  Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.

• Kværner, Ane Sørlie; Birkeland, Einar Elvbakken; Bucher-Johannessen, Cecilie; Vinberg, Elina; Nordby, Jan Inge & Kangas, Harri [Vis alle 27 forfattere av denne artikkelen] (2021). The CRCbiome study: a large prospective cohort study examining the role of lifestyle and the gut microbiome in colorectal cancer screening participants. BMC Cancer. 21. doi: 10.1186/s12885-021-08640-8. Fulltekst i vitenarkiv Vis sammendrag

  Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50–74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

• Mattingsdal, Morten; Ebenesersdóttir, Sigríður Sunna; Moore, Kristjan H. S.; Andreassen, Ole Andreas; Hansen, Thomas F. & Werge, Thomas [Vis alle 12 forfattere av denne artikkelen] (2021). The genetic structure of Norway. European Journal of Human Genetics. ISSN 1018-4813. 29. doi: 10.1038/s41431-021-00899-6. Fulltekst i vitenarkiv Vis sammendrag

  The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotypebased approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity, and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway’s long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been an isolated region in Norway, highlighting the open sea as a barrier to gene flow into Norway.

• Nakken, Sigve; Saveliev, Vladislav; Hofmann, Oliver; Møller, Pål; Myklebost, Ola & Hovig, Eivind (2021). Cancer Predisposition Sequencing Reporter (CPSR): A flexible variant report engine for high-throughput germline screening in cancer. International Journal of Cancer. ISSN 0020-7136. 149(11), s. 1–6. doi: 10.1002/ijc.33749. Fulltekst i vitenarkiv Vis sammendrag

  The value of high-throughput germline genetic testing is increasingly recognized inclinical cancer care. Disease-associated germline variants in cancer patients areimportant for risk management and surveillance, surgical decisions and can also havemajor implications for treatment strategies since many are in DNA repair genes. Withthe increasing availability of high-throughput DNA sequencing in cancer clinics andresearch, there is thus a need to provide clinically oriented sequencing reports forgermline variants and their potential therapeutic relevance on a per-patient basis. Tomeet this need, we have developed the Cancer Predisposition Sequencing Reporter(CPSR), an open-source computational workflow that generates a structured reportof germline variants identified in known cancer predisposition genes, highlightingmarkers of therapeutic, prognostic and diagnostic relevance. A fully automated vari-ant classification procedure based on more than 30 refined American College ofMedical Genetics and Genomics (ACMG) criteria represents an integral part of theworkflow. Importantly, the set of cancer predisposition genes profiled in the reportcan be flexibly chosen from more than 40 virtual gene panels established by scientificexperts, enabling customization of the report for different screening purposes andclinical contexts. The report can be configured to also list actionable secondary vari-ant findings, as recommended by ACMG. CPSR demonstrates comparable sensitivityand specificity for the detection of pathogenic variants when compared to otheralgorithms in the field. Technically, the tool is implemented in Python/R, and is freelyavailable through Docker technology. Source code, documentation, example reportsand installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr.

• Wise, Jillian; Nakken, Sigve; Steen, Chloe Beate; Vodak, Daniel; Trøen, Gunhild & Johannessen, Bjarne [Vis alle 24 forfattere av denne artikkelen] (2020). Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series. Blood Advances. ISSN 2473-9529. 4(9), s. 1859–1866. doi: 10.1182/bloodadvances.2019001325. Fulltekst i vitenarkiv Vis sammendrag

  • Diagnostic and relapse diffuse large B-cell lymphoma (DLBCL) biopsies reveal increased mutational burden/loss of heterozygosity in HLA-A. • Serially sampled tumor biopsies provide insight into therapeutic targets and evolutionary divergence in relapsed/refractory DLBCL.

• Tolios, Alexander; Rivas, Javier De Las; Hovig, Eivind; Trouillas, Patrick; Scorilas, Andreas & Mohr, Thomas (2020). Computational approaches in cancer multidrug resistance research: Identification of potential biomarkers, drug targets and drug-target interactions. Drug resistance updates. ISSN 1368-7646. 48:100662, s. 1–15. doi: 10.1016/j.drup.2019.100662. Fulltekst i vitenarkiv
• Dominguez-Valentin, Mev; Crosbie, Emma J.; Engel, Christoph; Aretz, Stefan; MacRae, Finlay & Winship, Ingrid [Vis alle 88 forfattere av denne artikkelen] (2020). Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report. Genetics in Medicine. ISSN 1098-3600. s. 1–8. doi: 10.1038/s41436-020-01029-1. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

• Olafsdottir, Elinborg J.; Borg, Åke; Jensen, Maj-Britt; Gerdes, Anne-Marie; Johansson, Anna L. V. & Barkardottir, Rosa B. [Vis alle 20 forfattere av denne artikkelen] (2020). Breast cancer survival in Nordic BRCA2 mutation carriers—unconventional association with oestrogen receptor status. British Journal of Cancer. ISSN 0007-0920. 123, s. 1608–1615. doi: 10.1038/s41416-020-01056-4. Fulltekst i vitenarkiv
• Waaler, Jo; Mygland, Line; Tveita, Anders Aune; Strand, Martin Frank; Solberg, Nina & Olsen, Petter Angell [Vis alle 19 forfattere av denne artikkelen] (2020). Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models. Communications Biology. 3. doi: 10.1038/s42003-020-0916-2. Fulltekst i vitenarkiv Vis sammendrag

  The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. Evidence for WNT/β-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/β-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Mechanistically, we demonstrate that the synergistic effect of tankyrase and checkpoint inhibitor treatment is dependent on loss of β-catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFNγ- and CD8+ T cell-mediated anti-tumor immune response. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome β-catenin-mediated resistance to immune checkpoint blockade in melanoma.

• Lavelle, Timothy J; Alver, Tine Norman; Heintz, Karen Marie; Wernhoff, Patrik; Nygaard, Vegard & Nakken, Sigve [Vis alle 10 forfattere av denne artikkelen] (2020). Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes. Cancers. 12(7), s. 1–20. doi: 10.3390/cancers12071719. Fulltekst i vitenarkiv Vis sammendrag

  The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.

• Dominguez-Valentin, Mev; Seppälä, Toni T.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay & Winship, Ingrid [Vis alle 45 forfattere av denne artikkelen] (2020). Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database. Journal of Clinical Medicine. 9(7). doi: 10.3390/jcm9072290. Fulltekst i vitenarkiv
• Ree, Anne Hansen; Nygaard, Vigdis; Pedersen, Kjetil Boye; Heinrich, Daniel; Dueland, Svein & Bergheim, Inger Riise [Vis alle 25 forfattere av denne artikkelen] (2020). Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer?the MetAction study. Acta Oncologica. ISSN 0284-186X. s. 1–10. doi: 10.1080/0284186X.2020.1742377. Fulltekst i vitenarkiv Vis sammendrag

  <i>Background</i>: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014–2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016–2019).<p><p> <i>Material and methods</i>: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints.<p><p> <i>Results</i>: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2–3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment.<p><p> <i>Conclusions</i>: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity <i>versus</i> resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies.

• Salgado, David; Béroud, Christophe; Armean, Irina M.; Baudis, Michael; Beltran, Sergi & Capella, Salvador [Vis alle 42 forfattere av denne artikkelen] (2020). The ELIXIR Human Copy Number Variations Community: Building bioinformatics infrastructure for research. F1000. 9:1229, s. 1–15. doi: 10.12688/f1000research.24887.1. Fulltekst i vitenarkiv
• Zhao, Sen; Agafonov, Oleg; Azab, Abdulrahman; Stokowy, Tomasz & Hovig, Eivind (2020). Accuracy and efficiency of germline variant calling pipelines for human genome data. Scientific Reports. 10:20222, s. 1–12. doi: 10.1038/s41598-020-77218-4. Fulltekst i vitenarkiv Vis sammendrag

  Advances in next-generation sequencing technology have enabled whole genome sequencing (WGS) to be widely used for identification of causal variants in a spectrum of genetic-related disorders, and provided new insight into how genetic polymorphisms affect disease phenotypes. The development of different bioinformatics pipelines has continuously improved the variant analysis of WGS data. However, there is a necessity for a systematic performance comparison of these pipelines to provide guidance on the application of WGS-based scientific and clinical genomics. In this study, we evaluated the performance of three variant calling pipelines (GATK, DRAGEN and DeepVariant) using the Genome in a Bottle Consortium, “synthetic-diploid” and simulated WGS datasets. DRAGEN and DeepVariant show better accuracy in SNP and indel calling, with no significant differences in their F1-score. DRAGEN platform offers accuracy, flexibility and a highly-efficient execution speed, and therefore superior performance in the analysis of WGS data on a large scale. The combination of DRAGEN and DeepVariant also suggests a good balance of accuracy and efficiency as an alternative solution for germline variant detection in further applications. Our results facilitate the standardization of benchmarking analysis of bioinformatics pipelines for reliable variant detection, which is critical in genetics-based medical research and clinical applications.

• Pace, Marta; Falappa, Matteo; Freschi, Andrea; Balzani, Edoardo; Berteotti, Chiara & Martire, Viviana Lo [Vis alle 13 forfattere av denne artikkelen] (2020). Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors. JCI Insight. 5(12), s. 1–18. doi: 10.1172/jci.insight.137495. Fulltekst i vitenarkiv

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• Gundersen, Sveinung; Faci, Pavel Vazquez; Bianchini, Federico; Baskaran, Joshua; Cheneby, Jeanne Marie & Hovig, Eivind [Vis alle 7 forfattere av denne artikkelen] (2026). fairtracks/omnipy: Omnipy v0.23.1. doi: 10.5281/ZENODO.21999005. Fulltekst i vitenarkiv
• Gundersen, Sveinung; Bianchini, Federico; Baskaran, Joshua; Chèneby, Jeanne; Fatima, Nazeefa & Hovig, Eivind (2026). fairtracks/fairtracks.net: FAIRtracks.net - ELIXIR3. doi: 10.5281/ZENODO.20089254. Fulltekst i vitenarkiv
• D’Altri, Teresa; Freeberg, Mallory Ann; Curwin, Amy J.; Alonso, Ana; Freitas, Ana T. & Capella-Gutierrez, Salvador [Vis alle 27 forfattere av denne artikkelen] (2025). The Federated European Genome–Phenome Archive as a global network for sharing human genomics data. Nature Genetics. ISSN 1061-4036. 57, s. 481–485. doi: 10.1038/s41588-025-02101-9. Fulltekst i vitenarkiv
• Nikolski, Macha; Hovig, Eivind; Al-Shahrour, Fatima; Blomberg, Niklas; Scollen, Serena & Valencia, Alfonso [Vis alle 7 forfattere av denne artikkelen] (2024). Roadmap for a European cancer data management and precision medicine infrastructure. Nature Cancer. 5, s. 367–372. doi: 10.1038/s43018-023-00717-6. Fulltekst i vitenarkiv
• Gundersen, Sveinung; Baskaran, Joshua; Bianchini, Federico; Boddu, Sanjay; Cheneby, Jeanne Marie & Drabløs, Finn Sverre [Vis alle 17 forfattere av denne artikkelen] (2023). Will you help us mobilise the abundance of functional genomics data for FAIR reuse in the age of pangenomes and AI? doi: 10.5281/ZENODO.22145365. Fulltekst i vitenarkiv
• Przybyła, Weronika; Trøen, Gunhild; Lai, Xiaoran; Samarakoon, Pubudu Saneth; Kaveh, Fatemeh & Hovig, Eivind [Vis alle 8 forfattere av denne artikkelen] (2023). Comparative whole genome copy number analysis of disseminated tumor cells and the primary tumor in high-risk neuroblastoma. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Frei, Oleksandr; Shadrin, Alexey; Rahman, Zillur; Lin, Aihua & Athanasiu, Lavinia [Vis alle 26 forfattere av denne artikkelen] (2022). The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: the MoBaPsychGen_v1 pipeline. Fulltekst i vitenarkiv
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Vis alle 116 forfattere av denne artikkelen] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), s. 885–887. doi: 10.1038/s41591-022-01777-4. Fulltekst i vitenarkiv
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Vis alle 53 forfattere av denne artikkelen] (2022). Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5). Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03518-0. Fulltekst i vitenarkiv
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Vis alle 53 forfattere av denne artikkelen] (2022). Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. Journal of Translational Medicine. 20(1), s. 1–11. doi: 10.1186/s12967-022-03432-5. Fulltekst i vitenarkiv Vis sammendrag

  Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

• Akdeniz, Bayram Cevdet; Mattingsdal, Morten; Valentin, Mev Dominguez; Frei, Oleksandr; Shadrin, Alexey & Puustusmaa, Mikk [Vis alle 11 forfattere av denne artikkelen] (2022). Implementation of polygenic risk score guided breast cancer prediction in Norwegian data. NSHG-PM 2022. Fulltekst i vitenarkiv
• Akdeniz, Bayram Cevdet; Bøen, Rune; Frei, Oleksandr; Hovig, Eivind; Andreassen, Ole & Sønderby, Ida Elken (2022). LARGE-SCALE ANALYSIS WITH SOFTWARE CONTAINERS IN ENIGMA-CNV–AN INTERNATIONAL WORKING GROUP TO STUDY RECURRENT COPY NUMBER VARIANTS AND BRAIN MEASURES. Neuropsychopharmacology, 2022. Fulltekst i vitenarkiv
• Stansberg, Christine; Hovig, Eivind; Willassen, Nils Peder & Jonassen, Inge (2021). Det er arbeidskrevende å gjøre data delbare! Khrono.no. ISSN 1894-8995. Fulltekst i vitenarkiv
• Dominguez-Valentin, Mev; Sampson, Julian R.; Møller, Pål; Seppälä, Toni T.; Plazzer, John-Paul & Nakken, Sigve [Vis alle 88 forfattere av denne artikkelen] (2021). Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum. International Journal of Cancer. ISSN 0020-7136. 148(2), s. 512–513. doi: 10.1002/ijc.33214. Fulltekst i vitenarkiv
• Kanduri, Chakravarthi; Sandve, Geir Kjetil Ferkingstad; Hovig, Eivind; De, Subhajyoti & Layer, Ryan (2021). Editorial: Genomic Colocalization and Enrichment Analyses. Frontiers in Genetics. 11. doi: 10.3389/fgene.2020.617876. Fulltekst i vitenarkiv
• Dominguez-Valentin, Mev; Sampson, Julian R.; Seppälä, Toni T.; Broeke, Sanne W. ten; Plazzer, John-Paul & Nakken, Sigve [Vis alle 88 forfattere av denne artikkelen] (2020). Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (Genetics in Medicine, (2020), 22, 1, (15-25), 10.1038/s41436-019-0596-9). Genetics in Medicine. ISSN 1098-3600. 22(9), s. 1569–1569. doi: 10.1038/s41436-020-0892-4. Fulltekst i vitenarkiv
• Bösl, Korbinian; Ghavidel, Fatemeh; Tekle, Kidane M; Kleppe, Rune; Hjerde, Erik & Drabløs, Finn [Vis alle 11 forfattere av denne artikkelen] (2020). End-to-End Data Management Toolkit for Norwegian Life Scientists. Fulltekst i vitenarkiv Vis sammendrag

  Major funding agencies require the successful planning and implementation of Data Management. In addition to obtaining funding, good Data Management also makes research more efficient, facilitates collaboration and saves time and resources. ELIXIR Norway and the Centre for Digital Life Norway have established an End-to-End toolkit, covering the whole data life cycle from proposal to publication, providing practical, existing solutions, available to Norwegian Life Scientists to make their research FAIR (Findable, Accessible, Interoperable and Reusable). We provide access to the Data Steward Wizard tool as one solution to identify data management needs, plan Data Management budgets and to produce a Data Management Plans (DMPs) according to the specifications by filling an interactive, well-documented questionnaire. NeLS - the Norwegian e-Infrastructure for Life Sciences is a versatile and backuped storage solution for Life Science data. NeLS is directly integrated with Galaxy, an open, web-based platform for accessible, reproducible, and transparent computational biological research, without the need of programming skills. We have further developed a integration of NeLS with FAIRDOMHub/SEEK, a resource platform for managing data-sets and models in projects and sharing at publication. ELIXIR maintains as variety of data deposition databases that are suited to host sensitive and non-sensitive data. Usage of this deposition repositories also maximises the visibility of published research.

• Stansberg, Christine; Willassen, Nils P; Thomassen, Gard O Sundby; Hovig, Johannes Eivind & Jonassen, Inge (2020). How open databases turn out to be crucial in the fight against Covid-19. NBS-nytt. ISSN 0801-3535. 4, s. 38–43. Fulltekst i vitenarkiv
• Fromm, Bastian; Domanska, Diana; Høye, Eirik; Ovchinnikov, Vladimir; Kang, Wenjing & Aparicio-Puerta, Ernesto [Vis alle 13 forfattere av denne artikkelen] (2020). Erratum: MirGeneDB 2.0: The metazoan microRNA complement (Nucleic Acids Research (2019) DOI: 10.1093/nar/gkz885). Nucleic Acids Research (NAR). ISSN 0305-1048. 48(1), s. D1172–D1172. doi: 10.1093/nar/gkz1016. Fulltekst i vitenarkiv
• Møller, Pål; Dominguez-Valentin, Mev; Rødland, Einar Andreas & Hovig, Eivind (2020). Correction: Causes for frequent pathogenic brca1 variants include low penetrance in fertile ages, recurrent de-novo mutations and genetic drift (Cancers, (2019), 11, 132, 10.3390/cancers11020132). Cancers. 12(2). doi: 10.3390/cancers12020410. Fulltekst i vitenarkiv
• Chèneby, Jeanne & Hovig, Eivind (2024). D3.2 - Integrative analysis of multiple data types within cancer portals. Zenodo. Fulltekst i vitenarkiv
• Corfield, Elizabeth Claire; Frei, Oleksandr; Shadrin, Alexey; Rahman, Zillur; Lin, Aihua & Athanasiu, Lavinia [Vis alle 26 forfattere av denne artikkelen] (2022). The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: MoBaPsychGen pipeline v.1. Cold Spring Harbor Laboratory Press (CSHL). doi: 10.1101/2022.06.23.496289. Fulltekst i vitenarkiv Vis sammendrag

  Background: The Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers. Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness. Methods: The MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation). Results: In total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 SNPs passed the MoBaPsychGen pipeline. The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs. Discussion: MoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

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