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The topography of mutational processes in breast cancer genomes.


ABSTRACT: Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

SUBMITTER: Morganella S 

PROVIDER: S-EPMC5001788 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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The topography of mutational processes in breast cancer genomes.

Morganella Sandro S   Alexandrov Ludmil B LB   Glodzik Dominik D   Zou Xueqing X   Davies Helen H   Staaf Johan J   Sieuwerts Anieta M AM   Brinkman Arie B AB   Martin Sancha S   Ramakrishna Manasa M   Butler Adam A   Kim Hyung-Yong HY   Borg Åke Å   Sotiriou Christos C   Futreal P Andrew PA   Campbell Peter J PJ   Span Paul N PN   Van Laere Steven S   Lakhani Sunil R SR   Eyfjord Jorunn E JE   Thompson Alastair M AM   Stunnenberg Hendrik G HG   van de Vijver Marc J MJ   Martens John W M JW   Børresen-Dale Anne-Lise AL   Richardson Andrea L AL   Kong Gu G   Thomas Gilles G   Sale Julian J   Rada Cristina C   Stratton Michael R MR   Birney Ewan E   Nik-Zainal Serena S  

Nature communications 20160502


Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome seq  ...[more]

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