Ole Christian Lingjærde

• Wang, Shixiong; Santacana-Font, Gemma; Kedra, Darek; Gilfillan, Siv; Tena-Chaves, David & Bergholtz, Helga [Vis alle 13 forfattere av denne artikkelen] (2025). The harmonized activities of HER2–HER3 heterodimer and deacetylated FOXA1 evade hormone response by regulating FOXA1 chromatin binding. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(20). doi: 10.1093/nar/gkaf1086. Fulltekst i vitenarkiv Vis sammendrag

  FOXA1 is a key transcription factor that mediates the effects of estrogen receptor (ER) and HER2 signaling in breast cancer. However, the mechanisms underlying FOXA1 regulation by HER2 and ER remain poorly understood. Here, we investigated FOXA1 regulation in cells with varying HER2 levels and its impact on endocrine therapy response. Chromatin interaction analyses revealed that high HER2 levels enhance FOXA1 binding to chromatin regions while reducing ER occupancy. Mechanistically, FOXA1 is acetylated by the histone acetyltransferase EP300 at the WD1 domain in ER-positive cells, attenuating its DNA binding at HER2-induced chromatin regions. Conversely, FOXA1 deacetylation—triggered by HER2/HER3 activation—increases its binding to ER-independent regions and promotes insensitivity to hormone therapy. In a luminal breast cancer patient-derived xenograft model, HER2/HER3 signaling increased FOXA1 chromatin binding and reduced sensitivity to ER-targeted treatment. We identify HDAC2 as a key deacetylase modulating FOXA1 acetylation and partially mediating the effects of HER2/HER3 signaling. Altogether, our findings highlight the significance of FOXA1 acetylation, regulated by the HER2/HER3–HDAC2–FOXA1 axis, in controlling FOXA1 chromatin binding and shaping breast cancer progression and therapy response. These insights may inform future therapeutic strategies.

• 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.

• Parissenti, Amadeo M.; Pritzker, Laura B.; Dahle, Maria Aanesland; Gythfeldt, Hedda; Masilamani, Twinkle & Theriault, Gabriel [Vis alle 11 forfattere av denne artikkelen] (2025). High mid-treatment tumour RNA disruption in patients with HER2-negative breast cancer is associated with improved disease-free survival after neoadjuvant chemotherapy. Breast Cancer Research. ISSN 1465-5411. 27( Breast Cancer Research). doi: 10.1186/s13058-025-02092-9. Fulltekst i vitenarkiv Vis sammendrag

  Background High tumour ribosomal RNA degradation (RNA disruption) during neoadjuvant chemotherapy has been associated with a post-treatment pathologic complete response (pCR) and improved disease-free survival (DFS) in breast cancer patients. We further assessed the relationship between tumour RNA disruption or other metrics and neoadjuvant chemotherapy outcome using data from the NeoAva clinical trial (NCT00773695). Methods Patients with early HER2-negative breast cancer received FEC-T chemotherapy ± bevacizumab in a randomized fashion. Biopsies were taken pre-treatment and after 12 and 25 weeks of chemotherapy. RNA and proteins extracted from the biopsies were used to compute the RNA disruption index (RDI) and to quantify levels of 210 proteins using protein array analysis at 12 weeks. Results Tumour RDI values were higher mid- and post-treatment than pre-treatment (p < 0.0001). Patients with tumour RDI values > 1.1 exhibited higher disease-free and breast cancer-specific survival than patients with RDI values ≤ 1.1 (p = 0.049 and 0.031, respectively). While RDI values were higher for patients on the bevacizumab-containing regimen (p = 0.003), this was not associated with improved survival. Survival on either regimen was not significantly associated with a post-treatment pCR or an improved residual cancer burden (RCB) score. Significant differences in apoptotic, EMT, Notch, G1-S checkpoint, and DNA damage response pathways were seen between high- and low-RDI tumours. Conclusions High tumour RNA disruption during neoadjuvant chemotherapy was associated with improved DFS and may better predict outcome than the post-treatment pCR rate or RCB. If validated as an independent predictor of chemotherapy outcome, RNA disruption assessments during treatment may prove informative in making treatment escalation or de-escalation decisions.

• Fjørtoft, Marit Otterlei; Garred, Øystein; Lingjærde, Ole Christian; Johannesen, Karin Teien; Ottestad, Lars & Bergheim, Inger Riise [Vis alle 29 forfattere av denne artikkelen] (2025). Single-cell analysis reveals tumour size as a key driver of immune cell profile alterations in primary breast tumours and corresponding lymph nodes. BJC Reports. 3(1). doi: 10.1038/s44276-025-00152-3. Fulltekst i vitenarkiv Vis sammendrag

  At diagnosis, 30–40% of women with breast cancer have metastases in sentinel (SN) or axillary lymph nodes (ALN). Nodal status is a strong prognostic factor and guides treatment decisions. Immune checkpoint inhibition has shown some efficacy, which can increase in the neoadjuvant setting. A better understanding of how tumour cells in primary tumours and metastatic lymph nodes shape the local immune microenvironment may provide clues for more individualized therapeutic interventions. Methods We conducted deep immunophenotypic analysis of 29 primary breast tumours and 36 lymph nodes from 38 patients with primary operable breast cancer. Results The immune profile of the primary tumour was not predictive of the lymph node immune profile or metastatic status. Primary tumours showed prominent CD8 T cell exhaustion and activated regulatory T cells, and the frequencies of these subsets were associated with tumour size. The immune cell profile in lymph nodes were different from the profile in primary tumours, except for the ALN+ nodes, which displayed a T-cell profile more similar to primary tumours. The frequencies of the T cell subsets in lymph nodeswere associated with metastatic size. Tumour cells from smaller metastases exhibited a distinct phenotype compared to those from larger tumour deposits, and the size of the tumour cell deposit impacted the local immune cell composition. Conclusion The tumour size of primary tumours and metastatic size in lymph nodes are the main drivers of changes in immune cell composition

• Røssevold, Andreas Hagen; Tekpli, Xavier; Lingjærde, Ole Christian; Russnes, Hege Elisabeth Giercksky; Vallon-Christersson, Johan & Borgen, Elin [Vis alle 12 forfattere av denne artikkelen] (2025). High tumor expression of CTLA4 identifies lymph node-negative basal-like breast cancer patients with excellent prognosis. Communications Medicine. 5(1), s. 1–13. doi: 10.1038/s43856-025-00865-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Tumor immune cell infiltration is a favorable prognostic factor in triple-negative breast cancer. Most triple-negative tumors belong to the aggressive basal-like subtype. We hypothesized that immune gene expression may identify low-risk patients for whom adjuvant chemotherapy can be de-escalated. Methods The expression of 753 immune-related genes was analyzed in tumor biopsies from 45 patients with basal-like disease and no lymph node metastases (Oslo1 cohort) and evaluated for prognostic value. Findings were validated in two independent cohorts. Oslo1 biopsies were also analyzed for tumor-infiltrating lymphocytes (TIL) and tertiary lymphoid structures (TLS). Results Here we show that a high expression of CTLA4 (above 63rd percentile) is associated with an excellent prognosis in the Oslo1 cohort. None of the patients in the CTLA4high group suffered disease recurrence (median follow-up 7.4 years) or breast cancer-related death (median follow-up 17.7 years). Analysis of the SCAN-B (n = 233; 97% without distant recurrence in CTLA4high group) and METABRIC cohorts (n = 155; 93% disease-specific survival in CTLA4high group) validates this finding, which also applies to patients who did not receive chemotherapy. CTLA4 expression correlates with TIL score and TLS levels (Oslo1 cohort), but no TILlow/CTLA4high patients died from breast cancer, suggesting that the CTLA4 readout identifies low-risk patients not captured by TIL assessment. Conclusions A high primary tumor expression of CTLA4 identifies patients with an excellent prognosis, for whom standard chemotherapy may be de-escalated or omitted.

• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Hamfjord, Julian; Nebdal, Daniel Johan Hammer; Lehtiö, J. & Lingjærde, Ole Christian [Vis alle 8 forfattere av denne artikkelen] (2025). Elevated KRAS protein level is associated with better survival in pancreatic cancer. BMC Cancer. 25. doi: 10.1186/s12885-025-14461-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Activating somatic KRAS mutations in hotspot loci occur almost universally (> 95%) in pancreatic ductal adenocarcinoma (PDAC). Both the presence of a KRAS mutation and high mRNA expression levels of KRAS in tumor tissue have been associated with worse outcome. Less is known about the expression of KRAS at the protein level and its association with clinical and molecular parameters. In the present study, we investigated the prognostic significance of the KRAS protein level and its relation to KRAS mutation status and the mRNA expression level. Methods A total of 41 PDAC tumors were screened for seven KRAS mutations (p.G12D, p.G12V, p.G12R, p.G12C, p.G12S, p.G13D, p.G12A) by the Wobble-enhanced ARMS method. Whole transcriptome and proteome profiles were obtained using mRNA microarrays (Agilent) and quantitative mass spectrometry-based proteomics (HiRIEF LC–MS/MS), respectively. The clinical outcome was overall survival (OS). Results KRAS mutations were identified in 88% of the tumors with p.G12D and p.G12V mutations being the most frequent. Tumors with p.G12V mutation had significantly higher KRAS mRNA expression than tumors with p.G12D, p.G12C, p.G12R or no mutation identified (P < 0.01). KRAS protein levels did not associate significantly to neither KRAS mRNA levels (Spearman’s rho = 0.18, P = 0.28) nor type of KRAS mutation. High KRAS protein level and mutation p.G12V were found to be significantly associated with better (P < 0.01) and worse OS (P < 0.05), respectively. Conclusions The KRAS protein level correlated poorly with KRAS mRNA expression level and was not significantly associated with the type of mutation present. Interestingly, we found that patients with high KRAS protein level in their tumors had a better clinical outcome.

• Stålberg, Stina Margrethe; Silwal-Pandit, Laxmi; Bastani, Nasser Ezzatkhah; Nebdal, Daniel J.H.; Lingjærde, Ole Christian & Skålhegg, Bjørn Steen [Vis alle 7 forfattere av denne artikkelen] (2024). Preoperative profiles of plasma amino acids and derivatives distinguish periampullary cancer and benign disease. BMC Cancer. 24(1). doi: 10.1186/s12885-024-12320-8. Fulltekst i vitenarkiv Vis sammendrag

  Periampullary cancers, including pancreatic ductal adenocarcinoma, ampullary-, cholangio-, and duodenal carcinoma, are frequently diagnosed in an advanced stage and are associated with poor overall survival. They are difficult to differentiate from each other and challenging to distinguish from benign periampullary disease preoperatively. To improve the preoperative diagnostics of periampullary neoplasms, clinical or biological markers are warranted. In this study, 28 blood plasma amino acids and derivatives from preoperative patients with benign (N = 45) and malignant (N = 72) periampullary disease were analyzed by LC-MS/MS. Principal component analysis and consensus clustering both separated the patients with cancer and the patients with benign disease. Glutamic acid had significantly higher plasma expression and 15 other metabolites significantly lower plasma expression in patients with malignant disease compared with patients having benign disease. Phenylalanine was the only metabolite associated with improved overall survival (HR = 0.50, CI 0.30–0.83, P < 0.01). Taken together, plasma metabolite profiles from patients with malignant and benign periampullary disease were significantly different and have the potential to distinguish malignant from benign disease preoperatively.

• Hamfjord, Julian; Guren, Tormod Kyrre; Glimerius, Bengt; Sorbye, Halfdan; Pfeiffer, Per & Dajani, Olav [Vis alle 11 forfattere av denne artikkelen] (2024). Exploring Early Kinetic Profiles of CEA, ctDNA and cfDNA in Patients With RAS-/BRAF-Mutated Metastatic Colorectal Cancer. Clinical colorectal cancer. ISSN 1533-0028. 24(2). doi: 10.1016/j.clcc.2024.11.004. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes. Materials and Methods: Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS). Results: Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P7), day 14 (P14), and day 49 (P49); slope from time-grid day 0 to 7 (S7), day 8 to 14 (S14), and day 15 to 49 (S49); and area under the curve from time-grid day 0 to 49 (AUC). Notably P49 and S49 for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (∼week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37). Conclusion: Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.

• Sharma, Abhibhav; Debik, Julia; Naume, Bjørn; Ohnstad, Hege Oma; Sahlberg, Guro Kristine Kleivi & Borgen, Elin [Vis alle 25 forfattere av denne artikkelen] (2024). Comprehensive multi-omics analysis of breast cancer reveals distinct long-term prognostic subtypes. Oncogenesis. 13(1), s. 1–13. doi: 10.1038/s41389-024-00521-6. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.

• Kildal, Wanja; Cyll, Karolina Urszula; Kalsnes, Joakim; Islam, Rakibul; Julbø, Frida Marie Ihle & Pradhan, Manohar [Vis alle 35 forfattere av denne artikkelen] (2024). Deep learning for automated scoring of immunohistochemically stained tumour tissue sections – Validation across tumour types based on patient outcomes. Heliyon. 10(13), s. 1–19. doi: 10.1016/j.heliyon.2024.e32529. Fulltekst i vitenarkiv Vis sammendrag

  We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9–98.5 %) for the nuclear model, 85.6 % (73.3–96.6 %) for the cytoplasmic model, and 78.4 % (75.5–84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.

• Ullern, Andreas; Holm, Kristian; Røssevold, Andreas Hagen; Andresen, Nikolai Kragøe; Bang, Corinna & Lingjærde, Ole Christian [Vis alle 9 forfattere av denne artikkelen] (2024). Gut microbiota diversity is prognostic and associated with benefit from chemo-immunotherapy in metastatic triple-negative breast cancer. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.13760. Fulltekst i vitenarkiv
• Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Quaghebeur, Claire; Gilje, Bjørnar; Boge, Beate & Gombos, Andrea [Vis alle 17 forfattere av denne artikkelen] (2024). Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: A randomized phase 2b trial. Journal for ImmunoTherapy of Cancer (JITC). 12:e007990(1), s. 1–12. doi: 10.1136/jitc-2023-007990. Fulltekst i vitenarkiv Vis sammendrag

  Background Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+ mBC). Doxorubicin and low- dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte- associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR + mBC. Methods Patients with HR+ mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/ m 2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/ nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death- ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers. Results Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross- over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross- over-arm. In the PP population (N=78) median PFS in the immune- chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo- only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor. Conclusion The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

• 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.

• Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko & Beckmann, Matthias W. [Vis alle 114 forfattere av denne artikkelen] (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics. ISSN 1018-4813. 31(5), s. 578–587. doi: 10.1038/s41431-022-01257-w. Fulltekst i vitenarkiv Vis sammendrag

  Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs

• Høland, Maren; Berg, Kaja Christine Graue; Eilertsen, Ina Andrassy; Bjerkehagen, Bodil; Kolberg, Matthias & Pedersen, Kjetil Boye [Vis alle 16 forfattere av denne artikkelen] (2023). Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets. EBioMedicine. 97:104829, s. 1–17. doi: 10.1016/j.ebiom.2023.104829. Fulltekst i vitenarkiv Vis sammendrag

  Background Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Methods Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. Findings MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. “Immune active” MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). “Immune deficient” MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). Interpretation Approximately half of MPNSTs belong to an “immune deficient” transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials.

• Isaksen, Kathrine Thuestad; Galleberg, Renate Berget; Mastroianni, Maria Adele; Rinde, Marit; Rusten, Leiv Sindre & Barzenje, Dlawer Abdulla [Vis alle 15 forfattere av denne artikkelen] (2023). The Geriatric Prognostic Index: a clinical prediction model for survival of older diffuse large B-cell lymphoma patients treated with standard immunochemotherapy. Haematologica. ISSN 0390-6078. 108(9), s. 2454–2466. doi: 10.3324/haematol.2022.282289. Fulltekst i vitenarkiv Vis sammendrag

  The International prognostic Index (IPI) is the most widely used clinical prediction model for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but may be suboptimal in older patients. We aimed to develop and externally validate a clinical prediction model for older, RCHOP- treated DLBCL patients by examining geriatric assessment and lymphoma-related parameters in real-world cohorts. A population-based training set of 365 R-CHOP-treated DLBCL patients ≥70 years was identified through the Cancer Registry of Norway. The external test set consisted of a population-based cohort of 193 patients. Data on candidate predictors were retrieved from the Cancer Registry and through review of clinical records. Cox regression models for 2-year overall survival were used for model selection. Activities of daily living, the Charlson Comorbidity Index, age, sex, albumin, stage, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level were identified as independent predictors and combined into a Geriatric Prognostic Index (GPI). The GPI demonstrated good discrimination (optimismcorrected C-index 0.752), and identified low-, intermediate- and high-risk groups with significantly different survivals (2- year overall survival, 94%, 65%, and 25%, respectively). At external validation, the continuous and grouped GPI demonstrated good discrimination (C-index 0.727 and 0.710, respectively) and the GPI groups had significantly different survivals (2-year overall survival 95%, 65%, and 44%, respectively). Both the continuous and grouped GPI showed better discrimination than the IPI, revised-IPI and National Comprehensive Cancer Network (NCCN)-IPI (C-index 0.621, 0.583, and 0.670, respectively). In conclusion, we have developed and externally validated a GPI for older DLBCL patients treated with R-CHOP that outperformed the IPI, revised-IPI and NCCN-IPI. A web-based calculator is available at https://wide.shinyapps. io/GPIcalculator/.

• Leich, E.; Brodtkorb, Marianne; Schmidt, T.; Altenbuchinger, M.; Lingjærde, Ole Christian & Lockmer, S. [Vis alle 14 forfattere av denne artikkelen] (2023). Gene expression and copy number profiling of follicular lymphoma biopsies from patients treated with first-line rituximab without chemotherapy. Leukemia and Lymphoma. ISSN 1042-8194. 64(12), s. 1927–1937. doi: 10.1080/10428194.2023.2240462. Fulltekst i vitenarkiv
• Silwal-Pandit, Laxmi; Stålberg, Stina Margrethe; Johansson, Henrik J.; Mermelekas, Georgios; Lothe, Inger Marie Bowitz & Skrede, Martina Landschoof [Vis alle 14 forfattere av denne artikkelen] (2022). Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome. Cancer Research Communications. 2(6), s. 434–446. doi: 10.1158/2767-9764.CRC-21-0100. Fulltekst i vitenarkiv Vis sammendrag

  Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry–based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium–specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM module, we defined an ECM-high and an ECM-low subgroup, where the ECM-high subgroup was associated with poor prognosis (median survival months: 15.3 vs. 22.9 months; log-rank test, P = 0.02). The ECM-high tumors were characterized by elevated epithelial–mesenchymal transition and glycolytic activities, and low oxidative phosphorylation, E2F, and DNA repair pathway activities. This study offers novel insights into the protein network underlying pancreatic cancer opening up for proteome precision medicine development. Significance: Pancreatic cancer lacks reliable biomarkers for prognostication and treatment of patients. We analyzed the proteome of pancreatic tumors, nonmalignant tissues of the pancreas and PDX-derived cell lines, and identified proteins that discriminate between patients with good and poor survival. The proteomics data also unraveled potential novel drug targets.

• Bjørklund, Sunniva; Aure, Miriam Ragle; Häkkinen, Jari; Vallon-Christersson, Johan; Kumar, Surendra & Evensen, Katrine Bull [Vis alle 34 forfattere av denne artikkelen] (2022). Subtype and cell type specific expression of lncRNAs provide insight into breast cancer. Communications Biology. 5(1), s. 1–14. doi: 10.1038/s42003-022-03559-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Long non-coding RNAs (lncRNAs) are involved in breast cancer pathogenesis through chromatin remodeling, transcriptional and post-transcriptional gene regulation. We report robust associations between lncRNA expression and breast cancer clinicopathological features in two population-based cohorts: SCAN-B and TCGA. Using co-expression analysis of lncRNAs with protein coding genes, we discovered three distinct clusters of lncRNAs. In silico cell type deconvolution coupled with single-cell RNA-seq analyses revealed that these three clusters were driven by cell type specific expression of lncRNAs. In one cluster lncRNAs were expressed by cancer cells and were mostly associated with the estrogen signaling pathways. In the two other clusters, lncRNAs were expressed either by immune cells or fibroblasts of the tumor microenvironment. To further investigate the cis-regulatory regions driving lncRNA expression in breast cancer, we identified subtype-specific transcription factor (TF) occupancy at lncRNA promoters. We also integrated lncRNA expression with DNA methylation data to identify long-range regulatory regions for lncRNA which were validated using ChiA-Pet-Pol2 loops. lncRNAs play an important role in shaping the gene regulatory landscape in breast cancer. We provide a detailed subtype and cell type-specific expression of lncRNA, which improves the understanding of underlying transcriptional regulation in breast cancer.

• Khadse, Anand; Haakensen, Vilde Drageset; Silwal-Pandit, Laxmi; Hamfjord, Julian; Micke, Patrick & Botling, Johan [Vis alle 10 forfattere av denne artikkelen] (2022). Prognostic Significance of the Loss of Heterozygosity of KRAS in Early-Stage Lung Adenocarcinoma. Frontiers in Oncology. 12. doi: 10.3389/fonc.2022.873532. Fulltekst i vitenarkiv Vis sammendrag

  Lung cancer is a common disease with a poor prognosis. Genomic alterations involving the KRAS gene are common in lung carcinomas, although much is unknown about how different mutations, deletions, and expressions influence the disease course. The first approval of a KRAS-directed inhibitor was recently approved by the FDA. Mutations in the KRAS gene have been associated with poor prognosis for lung adenocarcinomas, but implications of the loss of heterozygosity (LOH) of KRAS have not been investigated. In this study, we have assessed the LOH of KRAS in early-stage lung adenocarcinoma by analyzing DNA copy number profiles and have investigated the effect on patient outcome in association with mRNA expression and somatic hotspot mutations. KRAS mutation was present in 36% of cases and was associated with elevated mRNA expression. LOH in KRAS was associated with a favorable prognosis, more prominently in KRAS mutated than in wild-type patients. The presence of both LOH and mutation in KRAS conferred a better prognosis than KRAS mutation alone. For wild-type tumors, no difference in prognosis was observed between patients with and without LOH in KRAS. Our study indicates that LOH in KRAS is an independent prognostic factor that may refine the existing prognostic groups of lung adenocarcinomas.

• Mondragon, Jaime Abraham Castro; Aure, Miriam Ragle; Lingjærde, Ole Christian; Langerød, Anita; Martens, John WM & Børresen-Dale, Anne-Lise [Vis alle 8 forfattere av denne artikkelen] (2022). Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers. Nucleic Acids Research (NAR). ISSN 0305-1048. 50(21), s. 12131–12148. doi: 10.1093/nar/gkac1143. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Most cancer alterations occur in the noncoding portion of the human genome, where regulatory regions control gene expression. The discovery of noncoding mutations altering the cells’ regulatory programs has been limited to few examples with high recurrence or high functional impact. Here, we show that transcription factor binding sites (TFBSs) have similar mutation loads to those in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluate the combined effects of transcriptional and post-transcriptional alterations on the regulatory programs in cancers. The analysis of seven TCGA cohorts culminates with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that are associated with a cascading trans-effect deregulation on the cells’ regulatory programs. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predict 12 mature miRNAs (derived from 7 precursors) associated with the deregulation of their target gene networks. The predictions are enriched for cancer-associated protein-coding and miRNA genes and highlight cis-regulatory mutations associated with the dysregulation of key pathways associated with carcinogenesis. By combining transcriptional and post-transcriptional regulation of gene expression, our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients.

• Wolowczyk, Camilla; Neckmann, Ulrike; Aure, Miriam Ragle; Hall, Martina; Johannessen, Bjarne & Zhao, Sen [Vis alle 14 forfattere av denne artikkelen] (2022). NRF2 drives an oxidative stress response predictive of breast cancer. Free Radical Biology & Medicine. ISSN 0891-5849. 184, s. 170–184. doi: 10.1016/j.freeradbiomed.2022.03.029. Fulltekst i vitenarkiv Vis sammendrag

  Many breast cancer patients are diagnosed with small, well-differentiated, hormone receptor-positive tumors. Risk of relapse is not easily identified in these patients, resulting in overtreatment. To identify metastasis-related gene expression patterns, we compared the transcriptomes of the non-metastatic 67NR and metastatic 66cl4 cell lines from the murine 4T1 mammary tumor model. The transcription factor nuclear factor, erythroid 2-like 2 (NRF2, encoded by NFE2L2) was constitutively activated in the metastatic cells and tumors, and correspondingly a subset of established NRF2-regulated genes was also upregulated. Depletion of NRF2 increased basal levels of reactive oxygen species (ROS) and severely reduced ability to form primary tumors and lung metastases. Consistently, a set of NRF2-controlled genes was elevated in breast cancer biopsies. Sixteen of these were combined into a gene expression signature that significantly improves the PAM50 ROR score, and is an independent, strong predictor of prognosis, even in hormone receptor-positive tumors.

• Lien, Tonje Gulbrandsen; Ohnstad, Hege Oma; Lingjærde, Ole Christian; Vallon-Christersson, Johan; Aaserud, Marit & Sveli, My Anh Tu [Vis alle 12 forfattere av denne artikkelen] (2021). Sample preparation approach influences pam50 risk of recurrence score in early breast cancer. Cancers. 13(23). doi: 10.3390/cancers13236118. Fulltekst i vitenarkiv Vis sammendrag

  The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases.

• Haugen, Mads Haugland; Lingjærde, Ole Christian; Hedenfalk, Ingrid; Garred, Øystein; Borgen, Elin & Loman, Niklas [Vis alle 12 forfattere av denne artikkelen] (2021). Protein signature predicts response to neoadjuvant treatment with chemotherapy and bevacizumab in HER2-negative breast cancers. JCO Precision Oncology (JCO PO). 5, s. 286–306. doi: 10.1200/PO.20.00086. Fulltekst i vitenarkiv Vis sammendrag

  <p>PURPOSE: Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer (BC), there is an unmet need to identify patients who benefit from such treatment. <p>PATIENTS AND METHODS: In the NeoAva phase II clinical trial, patients (N = 132) with large (≥ 25 mm) human epidermal growth factor receptor 2 (HER2)-negative primary tumors were randomly assigned 1:1 to treatment with neoadjuvant chemotherapy (CTx) alone or in combination with bevacizumab (Bev plus CTx). The ratio of the tumor size after relative to before treatment was calculated into a continuous response scale. Tumor biopsies taken prior to neoadjuvant treatment were analyzed by reverse-phase protein arrays (RPPA) for expression levels of 210 BC-relevant (phospho-) proteins. Lasso regression was used to derive a predictor of tumor shrinkage from the expression of selected proteins prior to treatment. <p>RESULTS: We identified a nine-protein signature score named vascular endothelial growth factor inhibition response predictor (ViRP) for use in the Bev plus CTx treatment arm able to predict with accuracy pathologic complete response (pCR) (area under the curve [AUC] = 0.85; 95% CI, 0.74 to 0.97) and low residual cancer burden (RCB 0/I) (AUC = 0.80; 95% CI, 0.68 to 0.93). The ViRP score was significantly lower in patients with pCR (P < .001) and in patients with low RCB (P < .001). The ViRP score was internally validated on mRNA data and the resultant surrogate mRNA ViRP score significantly separated the pCR patients (P = .016). Similarly, the mRNA ViRP score was validated (P < .001) in an independent phase II clinical trial (PROMIX). <p>CONCLUSION: Our ViRP score, integrating the expression of nine proteins and validated on mRNA data both internally and in an independent clinical trial, may be used to increase the likelihood of benefit from treatment with bevacizumab combined with chemotherapy in patients with HER2-negative BC.

• Ask, Eivind Heggernes; Tschan-Plessl, Astrid; Gjerdingen, Thea Johanne; Hoel, Hanna Julie; Sætersmoen, Michelle Lu & Wiiger, Merete Thune [Vis alle 16 forfattere av denne artikkelen] (2021). A Systemic Protein Deviation Score Linked to PD-1+ CD8+ T Cell Expansion That Predicts Overall Survival in Diffuse Large B Cell Lymphoma. Med. ISSN 2666-6359. 2(2), s. 180–195. doi: 10.1016/j.medj.2020.10.006. Fulltekst i vitenarkiv
• Bjaanæs, Maria Moksnes; Nilsen, Gro; Halvorsen, Ann Rita; Russnes, Hege Elisabeth Giercksky; Solberg, Steinar & Jørgensen, Lars [Vis alle 9 forfattere av denne artikkelen] (2021). Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors. BMC Cancer. 21(1). doi: 10.1186/s12885-021-08811-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes. Methods Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, and regional copy number aberration were subsequently obtained and analyzed jointly with the gene expression data. Results The NSCLC tumors tissue displayed overall complex DNA copy number profiles with numerous recurrent aberrations. Despite histological differences, tissue samples from squamous cell carcinomas and adenocarcinomas had remarkably similar copy number patterns. The TP53-mutated lung adenocarcinomas displayed a highly aberrant genome, with significantly altered copy number profiles including gains, losses and focal complex events. The EGFR-mutant lung adenocarcinomas had specific arm-wise aberrations particularly at chromosome7p and 9q. A large number of genes displayed correlation between copy number and expression level, and the PI(3)K-mTOR pathway was highly enriched for such genes. Conclusions The genomic architecture in NSCLC tumors is complex, and particularly TP53-mutated lung adenocarcinomas displayed highly aberrant copy number profiles. We suggest to always include TP53-mutation status when studying copy number aberrations in NSCLC tumors. Copy number may further impact gene expression and alter cellular signaling pathways.

• Ben-Elazar, Shay; Aure, Miriam Ragle; Jonsdottir, Kristin; Leivonen, Suvi-Katri; Kristensen, Vessela N. & Janssen, Emiel [Vis alle 9 forfattere av denne artikkelen] (2021). miRNA normalization enables joint analysis of several datasets to increase sensitivity and to reveal novel miRNAs differentially expressed in breast cancer. PLoS Computational Biology. ISSN 1553-734X. 17(2). doi: 10.1371/JOURNAL.PCBI.1008608. Fulltekst i vitenarkiv Vis sammendrag

  Different miRNA profiling protocols and technologies introduce differences in the resulting quantitative expression profiles. These include differences in the presence (and measurability) of certain miRNAs. We present and examine a method based on quantile normalization, Adjusted Quantile Normalization (AQuN), to combine miRNA expression data from multiple studies in breast cancer into a single joint dataset for integrative analysis. By pooling multiple datasets, we obtain increased statistical power, surfacing patterns that do not emerge as statistically significant when separately analyzing these datasets. To merge several datasets, as we do here, one needs to overcome both technical and batch differences between these datasets. We compare several approaches for merging and jointly analyzing miRNA datasets. We investigate the statistical confidence for known results and highlight potential new findings that resulted from the joint analysis using AQuN. In particular, we detect several miRNAs to be differentially expressed in estrogen receptor (ER) positive versus ER negative samples. In addition, we identify new potential biomarkers and therapeutic targets for both clinical groups. As a specific example, using the AQuN-derived dataset we detect hsa-miR-193b-5p to have a statistically significant over-expression in the ER positive group, a phenomenon that was not previously reported. Furthermore, as demonstrated by functional assays in breast cancer cell lines, overexpression of hsa-miR-193b-5p in breast cancer cell lines resulted in decreased cell viability in addition to inducing apoptosis. Together, these observations suggest a novel functional role for this miRNA in breast cancer. Packages implementing AQuN are provided for Python and Matlab: https://github.com/YakhiniGroup/PyAQN.

• Hamfjord, Julian; Guren, Tormod Kyrre; Glimelius, Bengt; Sorbye, Halfdan; Pfeiffer, Per & Dajani, Olav [Vis alle 11 forfattere av denne artikkelen] (2021). Clinicopathological factors associated with tumour-specific mutation detection in plasma of patients with RAS-mutated or BRAF-mutated metastatic colorectal cancer. International Journal of Cancer. ISSN 0020-7136. 149(6), s. 1385–1397. doi: 10.1002/ijc.33672. Fulltekst i vitenarkiv Vis sammendrag

  Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.

• Rye, Inga Hansine; Huse, Kanutte; Josefsson, Sarah Elisabet; Kildal, Wanja; Danielsen, Håvard Emil Greger & Schlichting, Ellen [Vis alle 28 forfattere av denne artikkelen] (2021). Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Molecular Oncology. ISSN 1574-7891. 16(1), s. 88–103. doi: 10.1002/1878-0261.13047. Fulltekst i vitenarkiv Vis sammendrag

  Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single-cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B-cell and natural killer (NK)-cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T-cell immunoreceptor with Ig and ITIM domains)-positive T cells with suppressed TCR signaling compared with non-metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T-cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.

• 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.

• Liu, Jingjing; Smissen, Wendy J. C. Prager van der; Collee, Margriet J.; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Vis alle 82 forfattere av denne artikkelen] (2020). Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific Reports. 10:9688(1), s. 1–14. doi: 10.1038/s41598-020-65665-y. Fulltekst i vitenarkiv Vis sammendrag

  In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR=1.035, 95% CI=0.859–1.246, P=0.718 and OR=0.798, 95% CI=0.482–1.322, P=0.381 respectively), nor in specifc high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

• Pladsen, Arne Valebjørg; Nilsen, Gro; Rueda, Oscar M.; Aure, Miriam Ragle; Borgan, Ørnulf & Liestøl, Knut [Vis alle 18 forfattere av denne artikkelen] (2020). DNA copy number motifs are strong and independent predictors of survival in breast cancer. Communications Biology. 3. doi: 10.1038/s42003-020-0884-6. Fulltekst i vitenarkiv Vis sammendrag

  Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.

• Li, Constance H.; Prokopec, Stephenie D.; Sun, Ren X.; Yousif, Fouad; Schmitz, Nathaniel & Aure, Miriam Ragle [Vis alle 51 forfattere av denne artikkelen] (2020). Sex differences in oncogenic mutational processes. Nature Communications. 11:4330, s. 1–24. doi: 10.1038/s41467-020-17359-2. Fulltekst i vitenarkiv Vis sammendrag

  Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.

• Zapatka, Marc; Borozan, Ivan; Brewer, Daniel S.; Iskar, Murat; Grundhoff, Adam & Alawi, Malik [Vis alle 1 352 forfattere av denne artikkelen] (2020). The landscape of viral associations in human cancers. Nature Genetics. ISSN 1061-4036. 52(3), s. 320–330. doi: 10.1038/s41588-019-0558-9. Fulltekst i vitenarkiv
• Akdemir, Kadir C.; Le, Victoria T.; Chandran, Sahaana; Li, Yilong; Verhaak, Roel G. & Beroukhim, Rameen [Vis alle 1 401 forfattere av denne artikkelen] (2020). Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer. Nature Genetics. ISSN 1061-4036. 52(3), s. 294–305. doi: 10.1038/s41588-019-0564-y. Fulltekst i vitenarkiv
• Yuan, Yuan; Ju, Young Seok; Kim, Youngwook; Li, Jun; Wang, Yumeng & Yoon, Christopher J. [Vis alle 1 340 forfattere av denne artikkelen] (2020). Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nature Genetics. ISSN 1061-4036. 52(3), s. 342–352. doi: 10.1038/s41588-019-0557-x. Fulltekst i vitenarkiv
• Rodriguez-Martin, Bernardo; Alvarez, Eva G.; Baez-Ortega, Adrian; Zamora, Jorge; Supek, Fran & Demeulemeester, Jonas [Vis alle 1 441 forfattere av denne artikkelen] (2020). Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nature Genetics. ISSN 1061-4036. 52(3), s. 306–319. doi: 10.1038/s41588-019-0562-0. Fulltekst i vitenarkiv
• Bailey, Matthew H.; Meyerson, William U.; Dursi, L. Jonathan; Wang, Liang-Bo; Dong, Guanlan & Aure, Miriam Ragle [Vis alle 51 forfattere av denne artikkelen] (2020). Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples. Nature Communications. 11:4748, s. 1–27. doi: 10.1038/s41467-020-18151-y. Fulltekst i vitenarkiv Vis sammendrag

  The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

• Cortés-Ciriano, Isidro; Lee, Jake June-Koo; Xi, Ruibin; Jain, Dhawal; Jung, Youngsook L. & Yang, Lixing [Vis alle 1 398 forfattere av denne artikkelen] (2020). Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nature Genetics. ISSN 1061-4036. 52(3), s. 331–341. doi: 10.1038/s41588-019-0576-7. Fulltekst i vitenarkiv
• Hoff, Andreas Midbøe; Kraggerud, Sigrid M.; Alagaratnam, Sharmini; Berg, Kaja Christine Graue; Johannessen, Bjarne & Høland, Maren [Vis alle 11 forfattere av denne artikkelen] (2020). Frequent copy number gains of SLC2A3 and ETV1 in testicular embryonal carcinomas. Endocrine-Related Cancer. ISSN 1351-0088. 27(9), s. 457–468. doi: 10.1530/ERC-20-0064. Fulltekst i vitenarkiv Vis sammendrag

  Testicular germ cell tumours (TGCTs) appear as different histological subtypes or mixtures of these. They show similar, multiple DNA copy number changes, where gain of 12p is pathognomonic. However, few high-resolution analyses have been performed and focal DNA copy number changes with corresponding candidate target genes remain poorly described for individual subtypes. We present the first high-resolution DNA copy number aberration (CNA) analysis on the subtype embryonal carcinomas (ECs), including 13 primary ECs and 5 EC cell lines. We identified recurrent gains and losses and allele-specific CNAs. Within these regions, we nominate 30 genes that may be of interest to the EC subtype. By in silico analysis of data from 150 TGCTs from The Cancer Genome Atlas (TCGA), we further investigated CNAs, RNA expression, somatic mutations and fusion transcripts of these genes. Among primary ECs, ploidy ranged between 2.3 and 5.0, and the most common aberrations were DNA copy number gains at chromosome (arm) 7, 8, 12p, and 17, losses at 4, 10, 11, and 18, replicating known TGCT genome characteristics. Gain of whole or parts of 12p was found in all samples, including a highly amplified 100 kbp segment at 12p13.31, containing SLC2A3. Gain at 7p21, encompassing ETV1 , was the second most frequent aberration. In conclusion, we present novel CNAs and the genes located within these regions, where the copy number gain of SLC2A3 and ETV1 are of interest, and which copy number levels also correlate with expression in TGCTs.

• Analysis, of Whole Genomes Consortium ICGC/TCGA Pan-Cancer; Campbell, Peter J.; Getz, Gad; Korbel, Jan O.; Stuart, Joshua M. & Jennings, Jennifer L. [Vis alle 54 forfattere av denne artikkelen] (2020). Pan-cancer analysis of whole genomes. Nature. ISSN 0028-0836. 578(7793), s. 82–93. doi: 10.1038/s41586-020-1969-6. Fulltekst i vitenarkiv Vis sammendrag

  Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.

• Kyte, Jon A; Andresen, Nikolai Kragøe; Russnes, Hege Elisabeth Giercksky; Fretland, Signe Øien; Falk, Ragnhild Sørum & Lingjærde, Ole Christian [Vis alle 7 forfattere av denne artikkelen] (2020). ICON: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer. Journal of Translational Medicine. 18(1). doi: 10.1186/s12967-020-02421-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as “immunogenic” chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. Discussion ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198

• 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.

• Rubanova, Yulia; Shi, Ruian; Harrigan, Caitlin F.; Li, Roujia; Wintersinger, Jeff & Sahin, Nil [Vis alle 1 399 forfattere av denne artikkelen] (2020). Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig. Nature Communications. 11(1). doi: 10.1038/s41467-020-14352-7. Fulltekst i vitenarkiv
• Cmero, Marek; Yuan, Ke; Ong, Cheng Soon; Schröder, Jan; Adams, David J. & Anur, Pavana [Vis alle 1 396 forfattere av denne artikkelen] (2020). Inferring structural variant cancer cell fraction. Nature Communications. 11(1). doi: 10.1038/s41467-020-14351-8. Fulltekst i vitenarkiv
• Cmero, Marek; Yuan, Ke; Ong, Cheng Soon; Schröder, Jan; Adams, David J. & Anur, Pavana [Vis alle 1 396 forfattere av denne artikkelen] (2020). Inferring structural variant cancer cell fraction. Nature Communications. 11(1). doi: 10.1038/s41467-020-14351-8. Fulltekst i vitenarkiv
• Jiao, Wei; Atwal, Gurnit; Polak, Paz; Karlic, Rosa; Cuppen, Edwin & Al-Shahrour, Fatima [Vis alle 1 383 forfattere av denne artikkelen] (2020). A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns. Nature Communications. 11(1). doi: 10.1038/s41467-019-13825-8. Fulltekst i vitenarkiv
• Sieverling, Lina; Hong, Chen; Koser, Sandra D.; Ginsbach, Philip; Kleinheinz, Kortine & Hutter, Barbara [Vis alle 1 406 forfattere av denne artikkelen] (2020). Genomic footprints of activated telomere maintenance mechanisms in cancer. Nature Communications. 11(1). doi: 10.1038/s41467-019-13824-9. Fulltekst i vitenarkiv
• Gythfeldt, Hedda von der Lippe; Lien, Tonje Gulbrandsen; Tekpli, Xavier; Silwal-Pandit, Laxmi; Borgen, Elin & Garred, Øystein [Vis alle 15 forfattere av denne artikkelen] (2020). Immune phenotype of tumor microenvironment predicts response to bevacizumab in neoadjuvant treatment of ER-positive breast cancer. International Journal of Cancer. ISSN 0020-7136. 147(9), s. 2515–2525. doi: 10.1002/ijc.33108. Fulltekst i vitenarkiv Vis sammendrag

  Antiangiogenic drugs are potentially a useful supplement to neoadjuvant chemotherapy for a subgroup of patients with human epidermal growth factor receptor 2 (HER2) negative breast cancer, but reliable biomarkers for improved response are lacking. Here, we report on a randomized phase II clinical trial to study the added effect of bevacizumab in neoadjuvant chemotherapy with FEC100 (5‐fluorouracil, epirubicin and cyclophosphamide) and taxanes (n = 132 patients). Gene expression from the tumors was obtained before neoadjuvant treatment, and treatment response was evaluated by residual cancer burden (RCB) at time of surgery. Bevacizumab increased the proportion of complete responders (RCB class 0) from 5% to 20% among patients with estrogen receptor (ER) positive tumors (P = .02). Treatment with bevacizumab was associated with improved 8‐year disease‐free survival (P = .03) among the good responders (RCB class 0 or I). Patients treated with paclitaxel (n = 45) responded better than those treated with docetaxel (n = 21; P = .03). Improved treatment response was associated with higher proliferation rate and an immune phenotype characterized by high presence of classically activated M1 macrophages, activated NK cells and memory activated CD4 T cells. Treatment with bevacizumab increased the number of adverse events, including hemorrhage, hypertension, infection and febrile neutropenia, but despite this, the ECOG status was not affected.

• Bhandari, Vinayak; Li, Constance H.; Bristow, Robert G.; Boutros, Paul C.; Aaltonen, Lauri A. & Abascal, Federico [Vis alle 1 328 forfattere av denne artikkelen] (2020). Divergent mutational processes distinguish hypoxic and normoxic tumours. Nature Communications. 11(1). doi: 10.1038/s41467-019-14052-x. Fulltekst i vitenarkiv
• Zhang, Yiqun; Chen, Fengju; Fonseca, Nuno A.; He, Yao; Fujita, Masashi & Nakagawa, Hidewaki [Vis alle 1 465 forfattere av denne artikkelen] (2020). High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations. Nature Communications. 11(1). doi: 10.1038/s41467-019-13885-w. Fulltekst i vitenarkiv
• Steen, Chloe Beate; Leich, Ellen; Myklebust, June Helen; Lockmer, Sandra; Wise, Jillian & Wahlin, Björn Engelbrekt [Vis alle 14 forfattere av denne artikkelen] (2019). A clinico-molecular predictor identifies follicular lymphoma patients at risk of early transformation after first-line immunotherapy. Haematologica. ISSN 0390-6078. 104(10), s. 460–464. doi: 10.3324/haematol.2018.209080. Fulltekst i vitenarkiv
• Øjlert, Åsa Kristina; Halvorsen, Ann Rita; Nebdal, Daniel J.H.; Lund-Iversen, Marius; Solberg, Steinar & Brustugun, Odd Terje [Vis alle 8 forfattere av denne artikkelen] (2019). The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery. Molecular Oncology. ISSN 1574-7891. 13(5), s. 1166–1179. doi: 10.1002/1878-0261.12475. Fulltekst i vitenarkiv Vis sammendrag

  The impact of the tumor immune microenvironment on overall survival in non‐small cell lung cancer (NSCLC) has been studied, but there is little information on its relevance for risk of relapse after surgery. Understanding more about the immune microenvironment in previously untreated NSCLC could help in identifying high‐risk patients and patients more likely to benefit from neoadjuvant/adjuvant immunotherapy. Here, we examined gene expression in 399 surgically derived NSCLC samples and 47 samples from normal lung, using Agilent microarray and RNA sequencing. In 335 of the tumor samples, programmed death‐ligand 1 (PD‐L1) expression was evaluated by immunohistochemistry. Gene expression was used to estimate content of immune cells and to calculate an immune score. Properties of the immune microenvironment, and its impact on prognosis, were compared in histological subgroups and gene expression subtypes. Tumors with an active immune microenvironment were found for both adenocarcinomas (AD) and squamous cell carcinomas (SCC). In AD, high immune score and high estimates of several immune cell types belonging to the adaptive immune system were associated with better progression‐free survival (PFS), while in SCC, no association between immune characteristics and PFS was found. The immune microenvironment, including PD‐L1 expression, and its impact on prognosis showed clear differences in AD and SCC gene expression subtypes. In conclusion, the NSCLC immune microenvironment is predictive of prognosis after surgery. Lung AD and SCC gene expression subtypes should be investigated as potential prognostic biomarkers in patients treated with immune checkpoint inhibitors.

• Lindholm, Evita Maria; Aure, Miriam Ragle; Haugen, Mads Haugland; Sahlberg, Kristine Kleivi; Kristensen, Vessela N. & Nebdal, Daniel J.H. [Vis alle 9 forfattere av denne artikkelen] (2019). miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer. Molecular Oncology. ISSN 1574-7891. 13(10), s. 2278–2296. doi: 10.1002/1878-0261.12561. Fulltekst i vitenarkiv Vis sammendrag

  One of the hallmarks of cancer is sustained angiogenesis. Favorable results have been reported in some breast cancer (BC) patients receiving antiangiogenic therapy with bevacizumab (Bev) in combination with chemotherapy, and further knowledge on how Bev can be optimally combined with conventional treatment to increase efficacy is strongly needed. In this randomized, neoadjuvant phase II clinical trial, 132 patients with HER2‐negative, nonmetastatic BC were treated with Bev in combination with sequential chemotherapy. Biopsies were sampled before treatment, after 12 weeks with anthracycline and after taxane therapy at week 25. MicroRNA (miRNA) expression profiling was performed on biopsies from each time point. Altogether, 241 biopsies were analyzed with the aim of identifying miRNA‐based biomarkers of response to therapy. Results from the miRNA analyses were reported for the ER‐positive cohort, which were previously demonstrated to benefit from antiangiogenic therapy in this study. For both treatment arms of this cohort, significantly different expression was observed for 217 miRNAs between objective responding and nonresponding patients before treatment initiation. These miRNAs have been linked to regulation of epithelial–mesenchymal transition, metastasis, and tumor growth, among other processes. Bev in combination with chemotherapy resulted in similar miRNA changes to chemotherapy alone. However, the deregulation of miRNA expression occurred earlier in the Bev arm. In both arms, tumor suppressor miRNAs were found upregulated after treatment, while oncogenic miRNAs were downregulated in the Bev arm. Patients responding to Bev showed a strong correlation between deregulated miRNAs and decreased proliferation score during the course of treatment, with downregulation of miR‐4465 as the strongest indicator of reduced proliferation. Integrative analyses at miRNA‐, gene‐, and protein expression further indicated a longitudinal decrease in proliferation. Altogether, the results indicate that proliferation might represent a predictive factor for increased Bev sensitivity, which may aid in the identification of patients who could potentially benefit from Bev.

• Johansson, Henrik J.; Socciarelli, Fabio; Vacanti, Nathaniel M.; Haugen, Mads Haugland; Zhu, Yafeng & Siavelis, Ioannis [Vis alle 36 forfattere av denne artikkelen] (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications. 10:1600, s. 1–14. doi: 10.1038/s41467-019-09018-y. Fulltekst i vitenarkiv Vis sammendrag

  In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.

• Hamfjord, Julian; Guren, Tormod Kyrre; Dajani, Olav; Johansen, Julia Sidenius; Glimelius, Bengt & Sorbye, Halfdan [Vis alle 12 forfattere av denne artikkelen] (2019). Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy. Annals of Oncology. ISSN 0923-7534. 30(7), s. 1088–1095. doi: 10.1093/annonc/mdz139. Fulltekst i vitenarkiv Vis sammendrag

  Background: Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. Patients and methods: This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). Results: cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050–1 645 000) for B2M and 5959 alleles/ml (555–854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51–2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). Conclusion: cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response.

• Nygård, Ståle; Lingjærde, Ole Christian; Caldas, Carlos; Hovig, Eivind; Børresen-Dale, Anne-Lise & Helland, Åslaug [Vis alle 7 forfattere av denne artikkelen] (2019). PathTracer: High-sensitivity detection of differential pathway activity in tumours. Scientific Reports. 9:16332, s. 1–8. doi: 10.1038/s41598-019-52529-3. Fulltekst i vitenarkiv Vis sammendrag

  Gene expression profiling of tumours is an important source of information for cancer patient stratification. Detecting subtle alterations of gene expression remains a challenge, however. Here, we propose a novel tool for high-sensitivity detection of differential pathway activity in tumours. For a pathway defined by a collection of genes, the samples are projected onto a low-dimensional manifold in the subspace spanned by those genes. For each sample, a score is next found by calculating the distance between each projected sample and the projection of a subgroup of reference samples. Depending on the aim of the analysis and the available data, the reference samples may represent e.g. normal tissue or tumour samples with a particular genotype or phenotype. The proposed tool, PathTracer, is demonstrated on gene expression data from 1952 invasive breast cancer samples, 10 DCIS, 9 benign samples and 144 tumour adjacent normal breast tissue samples. PathTracer scores are shown to predict survival, clinical subtypes, cellular proliferation and genomic instability. Furthermore, predictions are shown to outperform those obtained with other comparable methods.

• Terkelsen, Thilde; Haakensen, Vilde Drageset; Saldova, Radka; Gromov, Pavel; Hansen, Merete Kjær & Stockmann, Henning [Vis alle 12 forfattere av denne artikkelen] (2018). N-glycan signatures identified in tumor interstitial fluid and serum of breast cancer patients: association with tumor biology and clinical outcome. Molecular Oncology. ISSN 1574-7891. 12(6), s. 972–990. doi: 10.1002/1878-0261.12312. Fulltekst i vitenarkiv
• Våtsveen, Thea Kristin; Myhre, Marit Renee; Steen, Chloe Beate; Wälchli, Sébastien; Lingjærde, Ole Christian & Bai, Baoyan [Vis alle 14 forfattere av denne artikkelen] (2018). Artesunate shows potent anti-tumor activity in B-cell lymphoma. Journal of Hematology & Oncology. 11:23, s. 1–12. doi: 10.1186/s13045-018-0561-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. Methods We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice. Artesunate-treated B lymphoma cell lines were analyzed by functional assays, gene expression profiling, and protein expression to identify the mechanism of action. Results Drug screening identified artesunate as a highly potent anti-lymphoma drug.Artesunate induced potent growth suppression in most B lymphoma cells with an IC50 comparable to concentrations measured in serum from artesunate-treated malaria patients, while leaving normal B-cells unaffected. Artesunate markedly inhibited highly aggressive tumor growth in a xenograft model. Gene expression analysis identified endoplasmic reticulum (ER) stress and the unfolded protein response as the most affected pathways and artesunate-induced expression of the ER stress markers ATF-4 and DDIT3 was specifically upregulated in malignant B-cells, but not in normal B-cells. In addition, artesunate significantly suppressed the overall cell metabolism, affecting both respiration and glycolysis. Conclusions Artesunate demonstrated potent apoptosis-inducing effects across a broad range of B-cell lymphoma cell lines in vitro, and a prominent anti-lymphoma activity in vivo, suggesting it to be a relevant drug for treatment of B-cell lymphoma.

• Dean, Katharine Rose; Krauer, Fabienne; Walløe, Lars; Lingjærde, Ole Christian; Bramanti, Barbara & Stenseth, Nils Christian [Vis alle 7 forfattere av denne artikkelen] (2018). Human ectoparasites and the spread of plague in Europe during the Second Pandemic. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 115(6), s. 1304–1309. doi: 10.1073/pnas.1715640115. Fulltekst i vitenarkiv
• Møller, Elen Kristine; Nord, Silje; Wedge, David C; Lingjærde, Ole Christian; Silwal-Pandit, Laxmi & Gythfeldt, Hedda [Vis alle 19 forfattere av denne artikkelen] (2018). Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations. Genome Medicine. 10:92. doi: 10.1186/s13073-018-0601-y. Fulltekst i vitenarkiv Vis sammendrag

  Background Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels. Methods A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods. Results In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime. Conclusions Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy.

• Holte, Harald; Beiske, Klaus; Boyle, Merrill; Trøen, Gunhild; Blaker, Yngvild Nuvin & Myklebust, June [Vis alle 13 forfattere av denne artikkelen] (2018). The MCL35 gene expression proliferation assay predicts high-risk MCL patients in a Norwegian cohort of younger patients given intensive first line therapy. British Journal of Haematology. ISSN 0007-1048. s. 1–10. doi: 10.1111/bjh.15518. Fulltekst i vitenarkiv
• Rye, Inga Hansine; Trinh, Anne; Sætersdal, Anna Barbro; Nebdal, Daniel J.H.; Lingjærde, Ole Christian & Almendro, Vanessa [Vis alle 11 forfattere av denne artikkelen] (2018). Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. Molecular Oncology. ISSN 1574-7891. s. 1–18. doi: 10.1002/1878-0261.12375. Fulltekst i vitenarkiv Vis sammendrag

  Targeted therapy for patients with HER2‐positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single‐cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2‐targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease‐free survival and fewer long‐term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.

• Aure, Miriam Ragle; Vitelli, Valeria; Jernström, Sandra Johanna; Kumar, Surendra; Krohn, Marit & Due, Eldri Undlien [Vis alle 35 forfattere av denne artikkelen] (2017). Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome. Breast Cancer Research. ISSN 1465-5411. 19(44). doi: 10.1186/s13058-017-0812-y. Fulltekst i vitenarkiv Vis sammendrag

  Background Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. Methods Tumor tissue from 425 patients with primary breast cancer from the Oslo2 study was cut and blended, and divided into fractions for DNA, RNA and protein isolation and metabolomics, allowing the acquisition of representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a “cluster-of-clusters” approach with consensus clustering. Results Based on DNA copy number data, tumors were categorized into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and tumors were classified into ten subtypes using integrative clustering. The final consensus clustering that incorporated all aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype; these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significantly different outcomes, and in another a trend was observed. Conclusions The six integrated subtypes identified confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing knowledge of the heterogeneity of the luminal A subtype may add pivotal information to guide therapeutic choices, evidently bringing us closer to improved treatment for this largest subgroup of breast cancer.

• Russnes, Hege Elisabeth Giercksky; Lingjærde, Ole Christian; Børresen-Dale, Anne-Lise & Caldas, Carlos (2017). Breast cancer molecular stratification– from intrinsic subtypes to integrative clusters. American Journal of Pathology. ISSN 0002-9440. doi: 10.1016/j.ajpath.2017.04.022. Fulltekst i vitenarkiv

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• Yuan, Yuan; Ju, Young Seok; Kim, Youngwook; Li, Jun; Wang, Yumeng & Yoon, Christopher J. [Vis alle 1 339 forfattere av denne artikkelen] (2023). Publisher Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers (Nature Genetics, (2020), 52, 3, (342-352), 10.1038/s41588-019-0557-x). Nature Genetics. ISSN 1061-4036. 55(5), s. 893–893. doi: 10.1038/s41588-020-0587-4. Fulltekst i vitenarkiv
• Rheinbay, Esther; Nielsen, Morten Muhlig; Abascal, Federico; Wala, Jeremiah A.; Shapira, Ofer & Tiao, Grace [Vis alle 1 616 forfattere av denne artikkelen] (2023). Author Correction: Analyses of non-coding somatic drivers in 2,658 cancer whole genomes (Nature, (2020), 578, 7793, (102-111), 10.1038/s41586-020-1965-x). Nature. ISSN 0028-0836. 614(7948), s. E40–E40. doi: 10.1038/s41586-022-05599-9. Fulltekst i vitenarkiv
• Zapatka, Marc; Borozan, Ivan; Brewer, Daniel S.; Iskar, Murat; Grundhoff, Adam & Alawi, Malik [Vis alle 1 354 forfattere av denne artikkelen] (2023). Author Correction: The landscape of viral associations in human cancers (Nature Genetics, (2020), 52, 3, (320-330), 10.1038/s41588-019-0558-9). Nature Genetics. ISSN 1061-4036. 55(6), s. 1077–1077. doi: 10.1038/s41588-023-01316-y. Fulltekst i vitenarkiv
• Calabrese, Claudia; Davidson, Natalie R.; Demircioğlu, Deniz; Fonseca, Nuno A.; He, Yao & Kahles, André [Vis alle 1 459 forfattere av denne artikkelen] (2023). Author Correction: Genomic basis for RNA alterations in cancer (Nature, (2020), 578, 7793, (129-136), 10.1038/s41586-020-1970-0). Nature. ISSN 0028-0836. 614(7948), s. E37–E37. doi: 10.1038/s41586-022-05596-y. Fulltekst i vitenarkiv
• Yakneen, Sergei; Waszak, Sebastian Martin; Aminou, Brice; Bartolome, Javier; Boroevich, Keith A. & Boyce, Rich [Vis alle 1 439 forfattere av denne artikkelen] (2023). Author Correction: Butler enables rapid cloud-based analysis of thousands of human genomes (Nature Biotechnology, (2020), 38, 3, (288-292), 10.1038/s41587-019-0360-3). Nature Biotechnology. ISSN 1087-0156. 41(4), s. 577–577. doi: 10.1038/s41587-022-01554-1. Fulltekst i vitenarkiv
• Akdemir, Kadir C.; Le, Victoria T.; Chandran, Sahaana; Li, Yilong; Verhaak, Roel G. & Beroukhim, Rameen [Vis alle 1 405 forfattere av denne artikkelen] (2023). Author Correction: Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (Nature Genetics, (2020), 52, 3, (294-305), 10.1038/s41588-019-0564-y). Nature Genetics. ISSN 1061-4036. 55(6), s. 1079–1079. doi: 10.1038/s41588-023-01318-w. Fulltekst i vitenarkiv
• Yuan, Yuan; Ju, Young Seok; Kim, Youngwook; Li, Jun; Wang, Yumeng & Yoon, Christopher J. [Vis alle 1 340 forfattere av denne artikkelen] (2023). Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers (Nature Genetics, (2020), 52, 3, (342-352), 10.1038/s41588-019-0557-x). Nature Genetics. ISSN 1061-4036. 55(6), s. 1078–1078. doi: 10.1038/s41588-023-01317-x. Fulltekst i vitenarkiv
• Cortés-Ciriano, Isidro; Lee, Jake June-Koo; Xi, Ruibin; Jain, Dhawal; Jung, Youngsook L. & Yang, Lixing [Vis alle 1 402 forfattere av denne artikkelen] (2023). Author Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing (Nature Genetics, (2020), 52, 3, (331-341), 10.1038/s41588-019-0576-7). Nature Genetics. ISSN 1061-4036. 55(6), s. 1076–1076. doi: 10.1038/s41588-023-01315-z. Fulltekst i vitenarkiv
• Gerstung, Moritz; Jolly, Clemency; Leshchiner, Ignaty; Dentro, Stefan C.; Gonzalez, Santiago & Rosebrock, Daniel [Vis alle 1 440 forfattere av denne artikkelen] (2023). Author Correction: The evolutionary history of 2,658 cancers (Nature, (2020), 578, 7793, (122-128), 10.1038/s41586-019-1907-7). Nature. ISSN 0028-0836. 614(7948), s. E42–E42. doi: 10.1038/s41586-022-05601-4. Fulltekst i vitenarkiv
• Li, Yilong; Roberts, Nicola D.; Wala, Jeremiah A.; Shapira, Ofer; Schumacher, Steven E. & Kumar, Kiran [Vis alle 1 410 forfattere av denne artikkelen] (2023). Author Correction: Patterns of somatic structural variation in human cancer genomes (Nature, (2020), 578, 7793, (112-121), 10.1038/s41586-019-1913-9). Nature. ISSN 0028-0836. 614(7948), s. E38–E38. doi: 10.1038/s41586-022-05597-x. Fulltekst i vitenarkiv
• Alexandrov, Ludmil B.; Kim, Jaegil; Haradhvala, Nicholas J.; Huang, Mi Ni; Ng, Alvin Wei Tian & Wu, Yang [Vis alle 1 383 forfattere av denne artikkelen] (2023). Author Correction: The repertoire of mutational signatures in human cancer (Nature, (2020), 578, 7793, (94-101), 10.1038/s41586-020-1943-3). Nature. ISSN 0028-0836. 614(7948), s. E41–E41. doi: 10.1038/s41586-022-05600-5. Fulltekst i vitenarkiv
• Aaltonen, Lauri A.; Abascal, Federico; Abeshouse, Adam; Aburatani, Hiroyuki; Adams, David J. & Agrawal, Nishant [Vis alle 1 324 forfattere av denne artikkelen] (2023). Author Correction: Pan-cancer analysis of whole genomes (Nature, (2020), 578, 7793, (82-93), 10.1038/s41586-020-1969-6). Nature. ISSN 0028-0836. 614(7948), s. E39–E39. doi: 10.1038/s41586-022-05598-w. Fulltekst i vitenarkiv
• Yuan, Yuan; Ju, Young Seok; Kim, Youngwook; Li, Jun; Wang, Yumeng & Yoon, Christopher J. [Vis alle 1 340 forfattere av denne artikkelen] (2023). Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers (Nature Genetics, (2020), 52, 3, (342-352), 10.1038/s41588-019-0557-x). Nature Genetics. ISSN 1061-4036. 55(5), s. 892–892. doi: 10.1038/s41588-020-0629-y. Fulltekst i vitenarkiv
• Rodriguez-Martin, Bernardo; Alvarez, Eva G.; Baez-Ortega, Adrian; Zamora, Jorge; Supek, Fran & Demeulemeester, Jonas [Vis alle 1 445 forfattere av denne artikkelen] (2023). Author Correction: Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition (Nature Genetics, (2020), 52, 3, (306-319), 10.1038/s41588-019-0562-0). Nature Genetics. ISSN 1061-4036. 55(6), s. 1080–1080. doi: 10.1038/s41588-023-01319-9. Fulltekst i vitenarkiv
• Shuai, Shimin; Abascal, Federico; Amin, Samirkumar B.; Bader, Gary D.; Bandopadhayay, Pratiti & Barenboim, Jonathan [Vis alle 1 455 forfattere av denne artikkelen] (2022). Author Correction: Combined burden and functional impact tests for cancer driver discovery using DriverPower (Nature Communications, (2020), 11, 1, (734), 10.1038/s41467-019-13929-1). Nature Communications. 13(1). doi: 10.1038/s41467-022-32343-8. Fulltekst i vitenarkiv
• Cmero, Marek; Yuan, Ke; Ong, Cheng Soon; Schröder, Jan; Adams, David J. & Anur, Pavana [Vis alle 1 399 forfattere av denne artikkelen] (2022). Author Correction: Inferring structural variant cancer cell fraction (Nature Communications, (2020), 11, 1, (730), 10.1038/s41467-020-14351-8). Nature Communications. 13(1). doi: 10.1038/s41467-022-32338-5. Fulltekst i vitenarkiv
• Zhang, Yiqun; Chen, Fengju; Fonseca, Nuno A.; He, Yao; Fujita, Masashi & Nakagawa, Hidewaki [Vis alle 1 480 forfattere av denne artikkelen] (2022). Author Correction: High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations (Nature Communications, (2020), 11, 1, (736), 10.1038/s41467-019-13885-w). Nature Communications. 13(1). doi: 10.1038/s41467-022-32333-w. Fulltekst i vitenarkiv
• Paczkowska, Marta; Barenboim, Jonathan; Sintupisut, Nardnisa; Fox, Natalie S.; Zhu, Helen & Abd-Rabbo, Diala [Vis alle 1 459 forfattere av denne artikkelen] (2022). Author Correction: Integrative pathway enrichment analysis of multivariate omics data (Nature Communications, (2020), 11, 1, (735), 10.1038/s41467-019-13983-9). Nature Communications. 13(1). doi: 10.1038/s41467-022-32342-9. Fulltekst i vitenarkiv
• Jiao, Wei; Atwal, Gurnit; Polak, Paz; Karlic, Rosa; Cuppen, Edwin & Al-Shahrour, Fatima [Vis alle 1 385 forfattere av denne artikkelen] (2022). Author Correction: A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns (Nature Communications, (2020), 11, 1, (728), 10.1038/s41467-019-13825-8). Nature Communications. 13(1). doi: 10.1038/s41467-022-32329-6. Fulltekst i vitenarkiv
• Reyna, Matthew A.; Haan, David; Paczkowska, Marta; Verbeke, Lieven P. C.; Garcia, Miguel Vazquez & Kahraman, Abdullah [Vis alle 1 453 forfattere av denne artikkelen] (2022). Author Correction: Pathway and network analysis of more than 2500 whole cancer genomes (Nature Communications, (2020), 11, 1, (729), 10.1038/s41467-020-14367-0). Nature Communications. 13(1). doi: 10.1038/s41467-022-32334-9. Fulltekst i vitenarkiv
• Rubanova, Yulia; Shi, Ruian; Harrigan, Caitlin F.; Li, Roujia; Wintersinger, Jeff & Sahin, Nil [Vis alle 1 402 forfattere av denne artikkelen] (2022). Author Correction: Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig (Nature Communications, (2020), 11, 1, (731), 10.1038/s41467-020-14352-7). Nature Communications. 13(1). doi: 10.1038/s41467-022-32336-7. Fulltekst i vitenarkiv
• Bhandari, Vinayak; Li, Constance H.; Bristow, Robert G.; Boutros, Paul C.; Aaltonen, Lauri A. & Abascal, Federico [Vis alle 1 328 forfattere av denne artikkelen] (2022). Author Correction: Divergent mutational processes distinguish hypoxic and normoxic tumours (Nature Communications, (2020), 11, 1, (737), 10.1038/s41467-019-14052-x). Nature Communications. 13(1). doi: 10.1038/s41467-022-32339-4. Fulltekst i vitenarkiv
• Sieverling, Lina; Hong, Chen; Koser, Sandra D.; Ginsbach, Philip; Kleinheinz, Kortine & Hutter, Barbara [Vis alle 1 413 forfattere av denne artikkelen] (2022). Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer (Nature Communications, (2020), 11, 1, (733), 10.1038/s41467-019-13824-9). Nature Communications. 13(1). doi: 10.1038/s41467-022-32328-7. Fulltekst i vitenarkiv
• Bailey, Matthew H.; Meyerson, William U.; Dursi, Lewis Jonathan; Wang, Liang-Bo; Dong, Guanlan & Liang, Wen-Wei [Vis alle 1 451 forfattere av denne artikkelen] (2020). Author Correction: Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples (Nature Communications, (2020), 11, 1, (4748), 10.1038/s41467-020-18151-y). Nature Communications. 11(1). doi: 10.1038/s41467-020-20128-w. Fulltekst i vitenarkiv
• Silva, Anjali; Bassim, Sleiman; Sarkozy, Clementine; Mottok, Anja; Lackraj, Tracy & Jurinovic, Vindi [Vis alle 13 forfattere av denne artikkelen] (2019). Convergence of risk prediction models in follicular lymphoma. Haematologica. ISSN 0390-6078. 104(6). doi: 10.3324/haematol.2018.209031. Fulltekst i vitenarkiv
• Silwal-Pandit, Laxmi; Stålberg, Stina Margrethe; Mermelekas, G; Lothe, Inger Marie Bowitz; Skrede, Martina Landschoof & Dalsgaard, Astrid M. [Vis alle 11 forfattere av denne artikkelen] (2019). Proteomic Landscape of Pancreatic Ductal Adenocarcinoma. Fulltekst i vitenarkiv
• Bai, Baoyan; Vodák, Daniel; Nakken, Sigve; Wise, Jillian; Blaker, Yngvild Nuvin & Lingjærde, Ole Christian [Vis alle 18 forfattere av denne artikkelen] (2019). Deep profiling of genetic aberrations and clonal evolution in follicular lymphoma. Blood. ISSN 0006-4971. 134(1), s. 20–20. doi: 10.1182/blood-2019-128403. Fulltekst i vitenarkiv
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Vis alle 18 forfattere av denne artikkelen] (2019). Correction to: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors (Nature Communications, (2017), 8, 1, (1221), 10.1038/s41467-017-01355-0). Nature Communications. 10(1). doi: 10.1038/s41467-019-08512-7. Fulltekst i vitenarkiv
• Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik & Zou, Xueqing [Vis alle 88 forfattere av denne artikkelen] (2019). Correction to: Landscape of somatic mutations in 560 breast cancer whole-genome sequences (Nature, (2016), 534, 7605, (47-54), 10.1038/nature17676). Nature. ISSN 0028-0836. 566(7742), s. E1–E1. doi: 10.1038/s41586-019-0883-2. Fulltekst i vitenarkiv
• Tabib, Mandar; Khan, Malik Muhammad Zaki Murtaza; Lingjærde, Ole Christian; Johannessen, Kjetil Andre; Rasheed, Adil & Fonn, Eivind [Vis alle 8 forfattere av denne artikkelen] (2018). Geilo Winter School in eScience on Artificial Intelligence. Fulltekst i vitenarkiv
• Kaveh, Fatemeh; Baumbusch, Lars Oliver; Nebdal, Daniel J.H.; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian & Edvardsen, Hege [Vis alle 8 forfattere av denne artikkelen] (2018). Correction: A systematic comparison of copy number alterations in four types of female cancer. BMC Cancer. 18(80). doi: 10.1186/s12885-017-3766-7. Fulltekst i vitenarkiv
• Dean, Katharine Rose; Krauer, Fabienne; Walløe, Lars; Lingjærde, Ole Christian; Bramanti, Barbara & Stenseth, Nils Christian [Vis alle 7 forfattere av denne artikkelen] (2018). Reply to Park et al.: Human ectoparasite transmission of plague during the Second Pandemic is still plausible. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 115(34), s. E7894–E7895. doi: 10.1073/pnas.1810221115. Fulltekst i vitenarkiv
• Tarabichi, Maxime; Martincorena, Iñigo; Gerstung, Moritz; Leroi, Armand M.; Markowetz, Florian & Spellman, Paul [Vis alle 10 forfattere av denne artikkelen] (2018). Neutral tumor evolution? Nature Genetics. ISSN 1061-4036. 50(12), s. 1630–1633. doi: 10.1038/s41588-018-0258-x. Fulltekst i vitenarkiv
• Hamfjord, Julian; Guren, Tormod Kyrre; Dajani, Olav; Glimelius, Bengt; Sorbye, Halfdan & Pfeiffer, Per [Vis alle 12 forfattere av denne artikkelen] (2018). Total circulating cell-free DNA (cfDNA) as a prognostic biomarker in metastatic colorectal cancer prior to first-line oxaliplatin-based chemotherapy. Annals of Oncology. ISSN 0923-7534. 29, s. v109–v109. doi: 10.1093/annonc/mdy149.025. Fulltekst i vitenarkiv
• Cheng, Jiqiu; Demeulemeester, Jonas; Wedge, David C.; Vollan, Hans Kristian Moen; Pitt, Jason J. & Russnes, Hege Elisabeth Giercksky [Vis alle 18 forfattere av denne artikkelen] (2018). Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors. Nature Communications. 9(1). doi: 10.1038/s41467-018-07842-2. Fulltekst i vitenarkiv

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