Faculty Collaboration Database

Pan-cancer analysis of whole genomes. Nature 2020 Feb;578(7793):82-93

Date

02/07/2020

Pubmed ID

32025007

Pubmed Central ID

PMC7025898

DOI

10.1038/s41586-020-1969-6

Scopus ID

2-s2.0-85079038817 (requires institutional sign-in at Scopus site)   1553 Citations

Abstract

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 promoter⁴; 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 evolution⁷; 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.

Author List

ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium

Authors

Akinyemi Ojesina MD, PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Proliferation
Cellular Senescence
Chromothripsis
Cloud Computing
DNA Mutational Analysis
Evolution, Molecular
Female
Genome, Human
Genomics
Germ-Line Mutation
High-Throughput Nucleotide Sequencing
Humans
Information Dissemination
Male
Mutagenesis
Mutation
Neoplasms
Oncogenes
Promoter Regions, Genetic
RNA Splicing
Reproducibility of Results
Telomerase
Telomere