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(1-3). 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 promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

ICGC-ARGO precision medicine: familial matters in pancreatic cancer

The International Cancer Genome Consortium–Accelerating Research in Genomic Oncology (ICGC-ARGO)1 will analyse the tumours of more than 100 000 patients with cancer during the next 10 years in a standardised way, using high-quality multiomic and clinical data (in particular outcome and treatment information) to address outstanding questions that are vital to our quest to defeat cancer (ie, the delineation of markers of prognosis, therapeutic response, and resistance). ICGC-ARGO aims to deliver a million patient-years of precision oncology knowledge, by making data available to the research community in a rapid and responsible way, to accelerate research into the causes, and control, of cancer. Here, we present the first report of a series of precision medicine-informed cases discussed by tumour boards within ICGC-ARGO programmes: two sisters, diagnosed with pancreatic ductal adenocarcinoma 7 years apart, whose disease was characterised by an uncommon clinical course; the somatic and germline profiling of these two sisters informed treatment decisions and risk management for a third sister who was not diagnosed with pancreatic ductal adenocarcinoma, but with thyroid cancer and meningioma