Journal Article

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Glodzik, Dominik, Davies, Helen, Easton, Douglas, Li, Yilong, Rye, Inga Hansine, Stratton, Michael R, Birney, Ewan, Thompson, Alastair M, Campbell, Peter J, Stunnenberg, Hendrik G, Nik-Zainal, Serena, Russnes, Hege, van de Vijver, Marc J, Zou, Xueqing, Simpson, Peter T, Lakhani, Sunil R, Diez-Perez, Javier, Brinkman, Arie B, Smid, Marcel, Morganella, Sandro, Børresen-Dale, Anne-Lise, Raine, Keiran, Staaf, Johan, Purdie, Colin A, Martens, John W M, Viari, Alain, Richardson, Andrea L, Alexandrov, Ludmil B, Evan, Gerard, Kong, Gu

2017

Overview

Serena Nik-Zainal and colleagues present a detailed analysis of somatic rearrangements in 560 breast cancers. They highlight 33 rearrangement hotspots characterized mainly by large tandem duplications and show that these hotspots are enriched in breast cancer germline susceptibility loci and breast-specific super-enhancer elements. Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 60 APPLIED LIFE SCIENCES / 631/208/212 / 631/67/1347 / 692/308/2056 / Agriculture / analysis / Animal Genetics and Genomics / Basic Medicine / Bioinformatics / Biological Science / Biomedicine / Breast cancer / Breast Neoplasms - genetics / Cancer and Oncology / Cancer och onkologi / Cancer Research / Care and treatment / Clinical Medicine / Computer Science / Development and progression / Disease susceptibility / DNA Breaks, Double-Stranded / DNA Repair - genetics / Female / Gene Expression - genetics / Gene Function / Gene mutation / Genetic aspects / Genetic Loci - genetics / Genome - genetics / Genomes / Grants / Health aspects / Human Genetics / Humans / Klinisk medicin / Life Sciences / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Methods / Mutagenesis / Mutation / Mutation - genetics / Regulatory Sequences, Nucleic Acid - genetics / Signatures / Studies / Transcriptome - genetics / Tumors