Recurrent and functional regulatory mutations in breast cancer

Esther Rheinbay, Prasanna Parasuraman, Jonna Grimsby, Grace Tiao, Jesse M. Engreitz, Jaegil Kim, Michael S. Lawrence, Amaro Taylor-Weiner, Sergio Rodriguez-Cuevas, Mara Rosenberg, Julian Hess, Chip Stewart, Yosef E. Maruvka, Petar Stojanov, Maria L. Cortes, Sara Seepo, Carrie Cibulskis, Adam Tracy, Trevor J. Pugh, Jesse Lee, Zongli Zheng, Leif W. Ellisen, A. John Iafrate, Jesse S. Boehm, Stacey B. Gabriel, Matthew Meyerson, Todd R. Golub, Jose Baselga, Alfredo Hidalgo-Miranda, Toshi Shioda, Andre Bernards, Eric S. Lander and Gad Getz ()
Additional contact information
Esther Rheinbay: The Broad Institute of MIT and Harvard
Prasanna Parasuraman: Massachusetts General Hospital Center for Cancer Research
Jonna Grimsby: The Broad Institute of MIT and Harvard
Grace Tiao: The Broad Institute of MIT and Harvard
Jesse M. Engreitz: The Broad Institute of MIT and Harvard
Jaegil Kim: The Broad Institute of MIT and Harvard
Michael S. Lawrence: The Broad Institute of MIT and Harvard
Amaro Taylor-Weiner: The Broad Institute of MIT and Harvard
Sergio Rodriguez-Cuevas: Instituto de Enfermedades de la Mama FUCAM, A.C.
Mara Rosenberg: The Broad Institute of MIT and Harvard
Julian Hess: The Broad Institute of MIT and Harvard
Chip Stewart: The Broad Institute of MIT and Harvard
Yosef E. Maruvka: The Broad Institute of MIT and Harvard
Petar Stojanov: The Broad Institute of MIT and Harvard
Maria L. Cortes: The Broad Institute of MIT and Harvard
Sara Seepo: The Broad Institute of MIT and Harvard
Carrie Cibulskis: The Broad Institute of MIT and Harvard
Adam Tracy: The Broad Institute of MIT and Harvard
Trevor J. Pugh: Princess Margaret Cancer Centre, University of Toronto, Toronto
Jesse Lee: Massachusetts General Hospital Center for Cancer Research
Zongli Zheng: Massachusetts General Hospital Center for Cancer Research
Leif W. Ellisen: Massachusetts General Hospital Center for Cancer Research
A. John Iafrate: Massachusetts General Hospital Center for Cancer Research
Jesse S. Boehm: The Broad Institute of MIT and Harvard
Stacey B. Gabriel: The Broad Institute of MIT and Harvard
Matthew Meyerson: The Broad Institute of MIT and Harvard
Todd R. Golub: The Broad Institute of MIT and Harvard
Jose Baselga: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Alfredo Hidalgo-Miranda: Instituto Nacional de Medicina Genómica
Toshi Shioda: Massachusetts General Hospital Center for Cancer Research
Andre Bernards: Massachusetts General Hospital Center for Cancer Research
Eric S. Lander: The Broad Institute of MIT and Harvard
Gad Getz: The Broad Institute of MIT and Harvard

Nature, 2017, vol. 547, issue 7661, 55-60

Abstract: 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: 2017
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DOI: 10.1038/nature22992

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