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Nature. 2017 Jul 6;547(7661):55-60. doi: 10.1038/nature22992. Epub 2017 Jun 28.

Recurrent and functional regulatory mutations in breast cancer.

Author information

1
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
2
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts 02129, USA.
3
Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts 02139, USA.
4
Instituto de Enfermedades de la Mama FUCAM, A.C., Mexico City 04980, Mexico.
5
Princess Margaret Cancer Centre, University Health Network and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
6
Harvard Medical School, Boston, Massachusetts 02115, USA.
7
Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
9
Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico.
10
Massachusetts General Hospital, Department of Pathology, Boston, Massachusetts 02114, USA.

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.

PMID:
28658208
PMCID:
PMC5563978
DOI:
10.1038/nature22992
[Indexed for MEDLINE]
Free PMC Article

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