Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 15
  • Item
    No Preview Available
    Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
    Nath, A ; Cosgrove, PA ; Mirsafian, H ; Christie, EL ; Pflieger, L ; Copeland, B ; Majumdar, S ; Cristea, MC ; Han, ES ; Lee, SJ ; Wang, EW ; Fereday, S ; Traficante, N ; Salgia, R ; Werner, T ; Cohen, AL ; Moos, P ; Chang, JT ; Bowtell, DDL ; Bild, AH (NATURE PORTFOLIO, 2021-05-24)
    The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To understand the selection of factors driving heterogeneity before and through adaptation to treatment, we profile single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during therapy. We analyze scRNA-seq data from two independent patient cohorts to reveal that HGSOC is driven by three archetypal phenotypes, defined as oncogenic states that describe the majority of the transcriptome variation. Using a multi-task learning approach to identify the biological tasks of each archetype, we identify metabolism and proliferation, cellular defense response, and DNA repair signaling as consistent cell states found across patients. Our analysis demonstrates a shift in favor of the metabolism and proliferation archetype versus cellular defense response archetype in cancer cells that received multiple lines of treatment. While archetypes are not consistently associated with specific whole-genome driver mutations, they are closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism and proliferation archetype as resistance is acquired to multiple lines of therapy.
  • Item
    Thumbnail Image
    Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer.
    Nath, A ; Cosgrove, P ; Copeland, B ; Mirsafian, H ; Christie, E ; Pflieger, L ; Majumdar, S ; Cristea, M ; Han, E ; Lee, S ; Wang, E ; Fereday, S ; Traficante, N ; Salgia, R ; Werner, T ; Cohen, A ; Moos, P ; Chang, J ; Bowtell, D ; Bild, A (AMER ASSOC CANCER RESEARCH, 2021-07-01)
    Abstract The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To uncover phenotypic changes associated with chemotherapy resistance, we profiled single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during patient treatment. Analysis of scRNA-seq data from two independent patient cohorts revealed that HGSOC is driven by three core archetypal phenotypes, defined as oncogenic tasks that describe the majority of the transcriptome variation. A multi-task learning approach to identify the biological tasks of each archetype identified metabolism and proliferation, cellular defense response, and DNA repair signaling. The metabolism and proliferation archetype evolved during treatment and was enriched in cancer cells from patients that received multiple-lines of treatment and had elevated tumor burden indicated by CA-125 levels. The emergence of archetypes was not consistently associated with specific whole-genome driver mutations. However, archetypes were closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism archetype as resistance is acquired to multiple lines of therapy. Citation Format: Aritro Nath, Patrick Cosgrove, Benjamin Copeland, Hoda Mirsafian, Elizabeth Christie, Lance Pflieger, Sumana Majumdar, Mihaela Cristea, Ernest Han, Stephen Lee, Edward Wang, Sian Fereday, Nadia Traficante, Ravi Salgia, Theresa Werner, Adam Cohen, Phillip Moos, Jeffrey Chang, David Bowtell, Andrea Bild. Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3141.
  • Item
    Thumbnail Image
    Therapeutic options for mucinous ovarian carcinoma
    Gorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
  • Item
    Thumbnail Image
    Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D
    Yang, X ; Song, H ; Leslie, G ; Engel, C ; Hahnen, E ; Auber, B ; Horvath, J ; Kast, K ; Niederacher, D ; Turnbull, C ; Houlston, R ; Hanson, H ; Loveday, C ; Dolinsky, JS ; LaDuca, H ; Ramus, SJ ; Menon, U ; Rosenthal, AN ; Jacobs, I ; Gayther, SA ; Dicks, E ; Nevanlinna, H ; Aittomaeki, K ; Pelttari, LM ; Ehrencrona, H ; Borg, A ; Kvist, A ; Rivera, B ; Hansen, TVO ; Djursby, M ; Lee, A ; Dennis, J ; Bowtell, DD ; Traficante, N ; Diez, O ; Balmana, J ; Gruber, SB ; Chenevix-Trench, G ; Jensen, A ; Kjaer, SK ; Hogdall, E ; Castera, L ; Garber, J ; Janavicius, R ; Osorio, A ; Golmard, L ; Vega, A ; Couch, FJ ; Robson, M ; Gronwald, J ; Domchek, SM ; Culver, JO ; de la Hoya, M ; Easton, DF ; Foulkes, WD ; Tischkowitz, M ; Meindl, A ; Schmutzler, RK ; Pharoah, PDP ; Antoniou, AC (OXFORD UNIV PRESS INC, 2020-12)
    BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
  • Item
    Thumbnail Image
    Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer
    Song, H ; Dicks, EM ; Tyrer, J ; Intermaggio, M ; Chenevix-Trench, G ; Bowtell, DD ; Traficante, N ; Brenton, J ; Goranova, T ; Hosking, K ; Piskorz, A ; van Oudenhove, E ; Doherty, J ; Harris, HR ; Rossing, MA ; Duerst, M ; Dork, T ; Bogdanova, N ; Modugno, F ; Moysich, K ; Odunsi, K ; Ness, R ; Karlan, BY ; Lester, J ; Jensen, A ; Kruger Kjaer, S ; Hogdall, E ; Campbell, IG ; Lazaro, C ; Pujara, MA ; Cunningham, J ; Vierkant, R ; Winham, SJ ; Hildebrandt, M ; Huff, C ; Li, D ; Wu, X ; Yu, Y ; Permuth, JB ; Levine, DA ; Schildkraut, JM ; Riggan, MJ ; Berchuck, A ; Webb, PM ; Cybulski, C ; Gronwald, J ; Jakubowska, A ; Lubinski, J ; Alsop, J ; Harrington, P ; Chan, I ; Menon, U ; Pearce, CL ; Wu, AH ; de Fazio, A ; Kennedy, CJ ; Goode, E ; Ramus, S ; Gayther, S ; Pharoah, P (BMJ PUBLISHING GROUP, 2021-05)
    PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
  • Item
    Thumbnail Image
    Prognostic gene expression signature for high-grade serous ovarian cancer
    Millstein, J ; Budden, T ; Goode, EL ; Anglesio, MS ; Talhouk, A ; Intermaggio, MP ; Leong, HS ; Chen, S ; Elatre, W ; Gilks, B ; Nazeran, T ; Volchek, M ; Bentley, RC ; Wang, C ; Chiu, DS ; Kommoss, S ; Leung, SCY ; Senz, J ; Lum, A ; Chow, V ; Sudderuddin, H ; Mackenzie, R ; George, J ; Fereday, S ; Hendley, J ; Traficante, N ; Steed, H ; Koziak, JM ; Kobel, M ; McNeish, IA ; Goranova, T ; Ennis, D ; Macintyre, G ; De Silva, DS ; Ramon y Cajal, T ; Garcia-Donas, J ; Hernando Polo, S ; Rodriguez, GC ; Cushing-Haugen, KL ; Harris, HR ; Greene, CS ; Zelaya, RA ; Behrens, S ; Fortner, RT ; Sinn, P ; Herpel, E ; Lester, J ; Lubinski, J ; Oszurek, O ; Toloczko, A ; Cybulski, C ; Menkiszak, J ; Pearce, CL ; Pike, MC ; Tseng, C ; Alsop, J ; Rhenius, V ; Song, H ; Jimenez-Linan, M ; Piskorz, AM ; Gentry-Maharaj, A ; Karpinskyj, C ; Widschwendter, M ; Singh, N ; Kennedy, CJ ; Sharma, R ; Harnett, PR ; Gao, B ; Johnatty, SE ; Sayer, R ; Boros, J ; Winham, SJ ; Keeney, GL ; Kaufmann, SH ; Larson, MC ; Luk, H ; Hernandez, BY ; Thompson, PJ ; Wilkens, LR ; Carney, ME ; Trabert, B ; Lissowska, J ; Brinton, L ; Sherman, ME ; Bodelon, C ; Hinsley, S ; Lewsley, LA ; Glasspool, R ; Banerjee, SN ; Stronach, EA ; Haluska, P ; Ray-Coquard, I ; Mahner, S ; Winterhoff, B ; Slamon, D ; Levine, DA ; Kelemen, LE ; Benitez, J ; Chang-Claude, J ; Gronwald, J ; Wu, AH ; Menon, U ; Goodman, MT ; Schildkraut, JM ; Wentzensen, N ; Brown, R ; Berchuck, A ; Chenevix-Trench, G ; DeFazio, A ; Gayther, SA ; Garcia, MJ ; Henderson, MJ ; Rossing, MA ; Beeghly-Fadiel, A ; Fasching, PA ; Orsulic, S ; Karlan, BY ; Konecny, GE ; Huntsman, DG ; Bowtell, DD ; Brenton, JD ; Doherty, JA ; Pharoah, PDP ; Ramus, SJ (ELSEVIER, 2020-09)
    BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
  • Item
    Thumbnail Image
    Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium
    Martins, FC ; Couturier, D-L ; Paterson, A ; Karnezis, AN ; Christine, C ; Nazeran, TM ; Odunsi, A ; Gentry-Maharaj, A ; Vrvilo, A ; Hein, A ; Talhouk, A ; Osorio, A ; Hartkopf, AD ; Brooks-Wilson, A ; DeFazio, A ; Fischer, A ; Hartmann, A ; Hernandez, BY ; McCauley, BM ; Karpinskyj, C ; de Sousa, CB ; Hogdall, C ; Tiezzi, DG ; Herpel, E ; Taran, FA ; Modugno, F ; Keeney, G ; Nelson, G ; Steed, H ; Song, H ; Luk, H ; Benitez, J ; Alsop, J ; Koziak, JM ; Lester, J ; Rothstein, JH ; de Andrade, JM ; Lundvall, L ; Paz-Ares, L ; Robles-Diaz, L ; Wilkens, LR ; Garcia, MJ ; Intermaggio, MP ; Alcaraz, M-L ; Brett, MA ; Beckmann, MW ; Jimenez-Linan, M ; Anglesio, M ; Carney, ME ; Schneider, M ; Traficante, N ; Pejovic, N ; Singh, N ; Le, N ; Sinn, P ; Ghatage, P ; Erber, R ; Edwards, R ; Vierkant, R ; Ness, RB ; Leung, S ; Orsulic, S ; Brucker, SY ; Kaufmann, SH ; Fereday, S ; Gayther, S ; Winham, SJ ; Kommoss, S ; Pejovic, T ; Longacre, TA ; McGuire, V ; Rhenius, V ; Sieh, W ; Shvetsov, YB ; Whittemore, AS ; Staebler, A ; Karlan, BY ; Rodriguez-Antona, C ; Bowtell, DD ; Goode, EL ; Hogdall, E ; Candido dos Reis, FJ ; Gronwald, J ; Chang-Claude, J ; Moysich, KB ; Kelemen, LE ; Cook, LS ; Goodman, MT ; Fasching, PA ; Crawford, R ; Deen, S ; Menon, U ; Huntsman, DG ; Kobel, M ; Ramus, SJ ; Pharoah, PDP ; Brenton, JD (SPRINGERNATURE, 2020-09-01)
    BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
  • Item
    Thumbnail Image
    Genomic footprints of activated telomere maintenance mechanisms in cancer
    Sieverling, L ; Hong, C ; Koser, SD ; Ginsbach, P ; Kleinheinz, K ; Hutter, B ; Braun, DM ; Cortes-Ciriano, I ; Xi, R ; Kabbe, R ; Park, PJ ; Eils, R ; Schlesner, M ; Brors, B ; Rippe, K ; Jones, DTW ; Feuerbach, L (NATURE PORTFOLIO, 2020-02-05)
    Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.
  • Item
    Thumbnail Image
    High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
    Zhang, Y ; Chen, F ; Fonseca, NA ; He, Y ; Fujita, M ; Nakagawa, H ; Zhang, Z ; Brazma, A ; Creighton, CJ (NATURE PUBLISHING GROUP, 2020-02-05)
    The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
  • Item
    Thumbnail Image
    Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis
    Carlevaro-Fita, J ; Lanzos, A ; Feuerbach, L ; Hong, C ; Mas-Ponte, D ; Pedersen, JS ; Johnson, R ; Abascal, F ; Amin, SB ; Bader, GD ; Barenboim, J ; Beroukhim, R ; Bertl, J ; Boroevich, KA ; Brunak, S ; Campbell, PJ ; Carlevaro-Fita, J ; Chakravarty, D ; Chan, CWY ; Chen, K ; Choi, JK ; Deu-Pons, J ; Dhingra, P ; Diamanti, K ; Feuerbach, L ; Fink, JL ; Fonseca, NA ; Frigola, J ; Gambacorti-Passerini, C ; Garsed, DW ; Gerstein, M ; Getz, G ; Gonzalez-Perez, A ; Guo, Q ; Gut, IG ; Haan, D ; Hamilton, MP ; Haradhvala, NJ ; Harmanci, AO ; Helmy, M ; Herrmann, C ; Hess, JM ; Hobolth, A ; Hodzic, E ; Hong, C ; Hornshoj, H ; Isaev, K ; Izarzugaza, JMG ; Johnson, TA ; Juul, M ; Juul, RI ; Kahles, A ; Kahraman, A ; Kellis, M ; Khurana, E ; Kim, J ; Kim, JK ; Kim, Y ; Komorowski, J ; Korbel, JO ; Kumar, S ; Lanzos, A ; Larsson, E ; Lawrence, MS ; Lee, D ; Lehmann, K-V ; Li, S ; Li, X ; Lin, Z ; Liu, EM ; Lochovsky, L ; Lou, S ; Madsen, T ; Marchal, K ; Martincorena, I ; Martinez-Fundichely, A ; Maruvka, YE ; McGillivray, PD ; Meyerson, W ; Muinos, F ; Mularoni, L ; Nakagawa, H ; Nielsen, MM ; Paczkowska, M ; Park, K ; Park, K ; Pedersen, JS ; Pich, O ; Pons, T ; Pulido-Tamayo, S ; Raphael, BJ ; Reimand, J ; Reyes-Salazar, I ; Reyna, MA ; Rheinbay, E ; Rubin, MA ; Rubio-Perez, C ; Sabarinathan, R ; Sahinalp, SC ; Saksena, G ; Salichos, L ; Sander, C ; Schumacher, SE ; Shackleton, M ; Shapira, O ; Shen, C ; Shrestha, R ; Shuai, S ; Sidiropoulos, N ; Sieverling, L ; Sinnott-Armstrong, N ; Stein, LD ; Stuart, JM ; Tamborero, D ; Tiao, G ; Tsunoda, T ; Umer, HM ; Uuskula-Reimand, L ; Valencia, A ; Vazquez, M ; Verbeke, LPC ; Wadelius, C ; Wadi, L ; Wang, J ; Warrell, J ; Waszak, SM ; Weischenfeldt, J ; Wheeler, DA ; Wu, G ; Yu, J ; Zhang, J ; Zhang, X ; Zhang, Y ; Zhao, Z ; Zou, L ; von Mering, C (NATURE PUBLISHING GROUP, 2020-02-05)
    Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.