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Nat Genet. 2017 Oct;49(10):1476-1486. doi: 10.1038/ng.3934. Epub 2017 Aug 21.

A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.
3
Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia.
6
Department of Radiation Oncology, Brigham &Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Department of Biology, MIT, Cambridge, Massachusetts, USA.
8
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
9
Departments of Medical Oncology, Pathology, and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
10
Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
11
Department of Oncology, McGill University, Montreal, Quebec, Canada.
12
Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge, UK.
13
Cancer Research UK Cambridge Centre, Cambridge, UK.
14
Department of Oncology, University of Cambridge Hutchison-MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK.
15
Van Andel Research Institute, Grand Rapids, Michigan, USA.
16
Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
17
Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, USA.
18
Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Bethesda, Maryland, USA.
19
Department of Human Genetics, Lady Davis Institute for Medical Research and Research Institute McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
20
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

PMID:
28825726
DOI:
10.1038/ng.3934
[Indexed for MEDLINE]

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