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Recurrent and functional regulatory mutations in breast cancer

Author(s)
Parasuraman, Prasanna; Tiao, Grace; Kim, Jaegil; Taylor-Weiner, Amaro; Rodriguez-Cuevas, Sergio; Rosenberg, Mara; Hess, Julian; Stewart, Chip; Maruvka, Yosef E.; Stojanov, Petar; Seepo, Sara; Cibulskis, Carrie; Tracy, Adam; Pugh, Trevor J.; Lee, Jesse; Zheng, Zongli; Ellisen, Leif W.; Iafrate, A. John; Boehm, Jesse S.; Baselga, Jose; Hidalgo-Miranda, Alfredo; Shioda, Toshi; Bernards, Andre; Engreitz, Jesse Michael; Lander, Eric Steven; Rheinbay, Esther; Lawrence, Michael; Cortes, Maria; Gabriel, Stacey; Golub, Todd; Getz, Gad Asher; Meyerson, Matthew L.; ... Show more Show less
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Abstract
Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.
Date issued
2017-06
URI
http://hdl.handle.net/1721.1/117280
Department
Broad Institute of MIT and Harvard; Harvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Biology
Journal
Nature
Publisher
Nature Publishing Group
Citation
Rheinbay, Esther et al. “Recurrent and Functional Regulatory Mutations in Breast Cancer.” Nature 547, 7661 (June 2017): 55–60
Version: Author's final manuscript
ISSN
0028-0836
1476-4687

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