Older age should not be a barrier to testing for somatic variants in homologous recombination DNA repair-related genes in patients with high-grade serous ovarian carcinoma

Background: Somatic pathogenic variants (PVs) in homologous recombination DNA repair (HR)-related genes found in high-grade serous ovarian carcinomas (HGSC) are not well-characterised in older patients (≥70 years). This may reflect low testing rates in older patients. Methods: Data from 1210 HGSC patients in AACR Project GENIE and 324 patients in an independent dataset INOVATe were analysed. Cases where somatic variants could be distinguished from germline variants were included, and analysis was restricted to those with a somatic TP53 variant, to ensure cases were HGSC. Results: Of 1210 patients in GENIE, 27% (n = 325) were aged ≥70 years at testing. Patients with somatic-only PVs in BRCA2 were older compared with BRCA1 (median 71 vs 60 years, p = 0.002). Median age for 21 patients with somatic-only PVs in 11 other HR-related genes ranged from 40 to 67 years. In older patients, 7% (n = 22) had somatic BRCA1/2 PVs, and 1% (n = 2) had PVs other HR-related genes; this rate was not significantly different to younger patients (BRCA2 PVs were again found in older patients compared with BRCA1 (median age: at testing, 70 vs 63 years; at diagnosis, 68 vs 60 years). Conclusions: The overall frequency of somatic-only PVs in HR-related genes was similar in older and younger patients with HGSC, highlighting the importance of somatic testing irrespective of age. Limiting somatic testing by age may exclude patients who could benefit from maintenance poly(ADP-ribose) polymerase (PARP) inhibitors

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.J.M.C.T. is supported by European Research Council (ERC) Starting Grant 716290 ‘SCUBA CANCERS’, Ramon y Cajal grant RYC-2014-14999 and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) grant SAF2015-66368-P. B.R.-M., E.G.A., M.S.G. and S.Z. are supported by PhD fellowships from Xunta de Galicia (Spain) ED481A-2016/151, ED481A-2017/299, ED481A-2017/306 and ED481A-2018/199, respectively. F.S. was supported by ERC Starting Grant 757700 ‘HYPER-INSIGHT’, MINECO grant BFU2017-89833-P ‘RegioMut’, and further acknowledges institutional funding from the MINECO Severo Ochoa award and from the CERCA Programme of the Catalan Government. Y.S.J. was supported by Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI16C2387). A.L.B. is supported by MINECO PhD fellowship BES-2016-078166. M.T. was supported by MINECO grant SAF2015-73916-JIN. R.B. received funding through the National Institutes of Health (U24CA210978 and R01CA188228). M.G.B. received funding through MINECO, AEI, Xunta de Galicia and FEDER (BFU2013-41554-P, BFU2016-78121-P, ED431F 2016/019). N.B. is supported by a My First AIRC grant from the Associazione Italiana Ricerca sul Cancro (number 17658). J.D. is a postdoctoral fellow of the Research Foundation Flanders (FWO) and the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement number 703594-DECODE). K.C. and Z.C. are supported by NIH R01 CA172652 and U41 HG007497. Z.C. is supported by an American Heart Association Institutional Data Fellowship Award (17IF33890015). P.A.W.E. is supported by Cancer Research UK. E.A.L. is supported by K01AG051791. I.M. is supported by Cancer Research UK (C57387/A21777). S.M.W. received funding through a SNSF Early Postdoc Mobility fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). J.W. received funding from the Danish Medical Research Council (DFF-4183-00233). J.O.K. is supported by an ERC Starting Grant. This work is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). H.H.K. is supported by grants from the National Institute of General Medical Sciences (P50GM107632 and 1R01GM099875). K.H.B. is supported by P50GM107632, R01CA163705 and R01GM124531. This work was supported by the TransTumVar project PN013600.. This work was supported by the Wellcome Trust grant 0980

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. 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 promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes