Pan-cancer analysis of whole genomes
Панканцерный анализ полных геномов
2020-02-05
SCID: 54.1/vvznzvet
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ChromothripsisPan-cancer analysisSomatic mutationsStructural variantsWhole-cancer genomes
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Abstract (AI)
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 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 .
Key Findings
1
Cancer genomes contained an average of 4–5 driver mutations when coding and non-coding elements were considered, but approximately 5% had no identified drivers.
2
Chromothripsis was frequently an early event in tumor evolution and, in acral melanoma, preceded most somatic point mutations while simultaneously affecting multiple cancer-associated genes.
3
Common and rare germline variants influenced somatic mutation patterns, including point mutations, structural variants, and somatic retrotransposition.
4
The PCAWG analyses identified cancer-driving non-coding mutations beyond TERT promoter alterations and characterized new mutational signatures and transcriptional consequences of somatic mutations.
5
The PCAWG consortium analyzed 2,658 matched tumor–normal whole-genome pairs spanning 38 cancer types using internationally shared computational resources.
6
Tumors with abnormal telomere maintenance often arose from tissues with low replicative activity and used multiple mechanisms to prevent critical telomere shortening.
Research Object
2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types
Research Subject
The genomic alterations, mutational processes, driver mutations, tumour evolution, and transcriptional consequences underlying cancer development
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2020-02-05
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