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

Abstract：

: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.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Glodzik D,Morganella S,Davies H,Simpson PT,Li Y,Zou X,Diez-Perez J,Staaf J,Alexandrov LB,Smid M,Brinkman AB,Rye IH,Russnes H,Raine K,Purdie CA,Lakhani SR,Thompson AM,Birney E,Stunnenberg HG,van de Vijver MJ,Marten

doi

10.1038/ng.3771

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

341-348

issue

3

eissn

1061-4036

issn

1546-1718

pii

ng.3771

journal_volume

49

pub_type

杂志文章

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