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

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: 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

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Prognostic role of substaging in T1G3 transitional cell carcinoma of the urinary bladder

This study was conducted to test a new substaging system in a population of patients with stage T1 bladder cancer (BC) at diagnosis and assess its prognostic role in terms of disease progression and disease-specific survival (DSS). Patients with primary stage T1G3 urothelial carcinoma of the bladder were stratified according to the following models: i) T1a [the tumour does not infiltrate the muscularis mucosae-vascular plexus, (MM-VP)]; T1b (the tumour partially infiltrates the MM-VP); and T1c (the tumour infiltrates and invades the MM-VP). ii) T1m (diameter of tumour infiltrating the lamina propria 640.5 mm under a high-resolution microscope; and T1e (diameter of tumour infiltrating the lamina propria >0.5 mm). Age, gender, tumour size and multifocality were not found to be of statistical significance. Using the T1a/T1b/T1c system, patients with stage T1a disease exhibited a 5- and 10-year progression rate of 13.3 and 20%, respectively, without reaching statistical significance. Moreover, patients with stage T1a disease exhibited a 5- and 10-year DSS of 93.3 and 73.3%, respectively, which was higher compared to T1b and T1c but not statistically significant. Using the T1m/T1e system, patients with stage T1m disease exhibited a disease progression rate of 8.3 and 16.7% at 5 and 10 years, respectively, which was not statistically significant. Moreover, patients in group T1m presented with DSS rates of 91.7 and 83.3% at 5 and 10 years, respectively, which were higher compared to those in the T1e group (71.4 and 60.7%), although not reaching statistical significance. In conclusion, in our study, neither of the two substaging systems of stage T1 BC reached the prognostic conventional significance level for tumour progression or DSS