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.
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Data used in this analysis were funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community's Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006; the Triple Negative project, funded by the Wellcome Trust (grant reference 077012/Z/05/Z); and the HER2+ project, funded by Institut National du Cancer (INCa) in France (grant nos. 226-2009, 02-2011, 41-2012, 144-2008 and 06-2012). J.W.M.M. received funding for this project through an ERC Advanced grant (no. 322737). G.K. is supported by National Research Foundation of Korea grants (NRF 2015R1A2A1A10052578). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01). D.G. is supported by the EU-FP7-SUPPRESSTEM project. S.N.-Z. is funded by a Wellcome Trust Intermediate Fellowship (WT100183MA) and is supported as a Wellcome Beit Fellow.
Integrated supplementary information
Hotspots of rearrangement signatures RS1 and RS3 identified through a PCF-based method. (a) Description of headers. (b) Summary of hotspots.
Genomic consequences of RS1 and RS3 duplications (related to Fig. 4). Numbers of duplications and transections of genomic elements, separately for RS1 and RS3, inside and outside of the hotspots.
Hotspots of other rearrangement signatures (RS2, RS4, RS5, RS6) identified through PCF-based method. (a) Description of headers. (b) Summary of hotspots.
Genomic features of the RS1 hotspots. Comparison with the rest of tandem-duplicated genome with respect to: breast cancer susceptibility SNPs, breast tissue super-enhancers, non-breast super-enhancers, known oncogenes, promoters, enhancers, broad fragile sites, narrow fragile sites. (a) Description of headers. (b) Associations.
Modeling the effects of RS1 tandem duplications on gene expression. Rows, coefficients used in the regression models. Columns, experiments with different sets of genes. In the table we show the fitted values of regression coefficients.
Hotspots of rearrangement signatures RS1 and RS3 identified through PCF-based method in ovarian tumors. (a) Description of headers. (b) Summary of hotspots.
About this article
Cancer Cell (2019)