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.
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L.Z.B. was supported by the Louis B. Mayer Foundation. L.W.E. was supported by grants from the Avon Breast Cancer Crusade and the Breast Cancer Research Foundation (BCRF). G.G. and J.K. were partially funded by the NIH TCGA Genome Data Analysis Center (U24CA143845). P.P., N.J.H., Y.E.M., and A.K. were funded by the startup funds of G.G. at Massachusetts General Hospital. A.D.D. was supported by grants from the Ludwig Center at Harvard and the Breast Cancer Research Foundation (BCRF). W.D.F. was supported by Susan G. Komen. G.G. was partly funded by the Paul C. Zamecnick, MD, Chair in Oncology at Massachusetts General Hospital.
T.R.G. is a cofounder of Foundation Medicine.
Supplementary Figures 1–16 and Supplementary Note 1. (PDF 6139 kb)
ClinVar annotations of pathogenicity are reported, along with LOH status. (XLSX 47 kb)
Association between the functional characterization of BRCA1/2 missense variants with LOH and signature 3. (XLSX 41 kb)
Signature 3 and putative biallelic inactivation of BRCA1/2 correlate with clinical annotations among rare missense variants. (XLSX 41 kb)
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Polak, P., Kim, J., Braunstein, L. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 49, 1476–1486 (2017). https://doi.org/10.1038/ng.3934
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