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

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.

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Figure 1: Characterization of four distinct mutational signatures in breast cancer.
Figure 2: Overall mutation rates, mutational signature contributions, and clinicopathological features per patient as sorted by descending signature 3 activity.
Figure 3: Signature 3 activity in tumors with somatic, germline, and epigenetic alterations in HR-pathway genes.
Figure 4: The association of RAD51C-promoter methylation with elevated signature 3 activity in basal-like tumors.
Figure 5: Analysis of genetic and epigenetic events in the top quartile of signature 3 activity (n = 248), focused on the largest racial subgroups in our cohort (white and African American).
Figure 6: A framework for enhancing the classification of BRCA1/2 germline missense variants using signature 3 (sig3) and biallelic inactivation.
Figure 7: Prediction accuracy of signature 3 (sig3) relative to established rearrangement-based HRD scores.

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Acknowledgements

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.

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P.P., J.K., and L.Z.B. conceived the work, performed analyses, and wrote the manuscript. R.K. and N.J.H. performed analyses and wrote the manuscript. G.T., D.R. and D.L. performed analyses. K.K. edited the manuscript. A.K., Y.E.M., and I.L. performed analyses and edited the manuscript. E.S.L. T.R.G., and A.Z. edited the manuscript. K.W.M. and A.O. wrote the manuscript. M.S.L. performed analysis and edited the manuscript. R.N.B. and C.C. provided data. D.A.H., L.W.E., and S.J.C. contributed scientific insight and edited the manuscript. P.W.L. and H.S. performed analysis and wrote the manuscript. A.D.D'A. conceived the work, contributed scientific insight, and edited the manuscript. W.D.F. and G.G. conceived the work, oversaw the analyses, and wrote the manuscript.

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Correspondence to Gad Getz.

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T.R.G. is a cofounder of Foundation Medicine.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Supplementary Note 1. (PDF 6139 kb)

Life Sciences Reporting Summary. (PDF 129 kb)

Supplementary Table 1

ClinVar annotations of pathogenicity are reported, along with LOH status. (XLSX 47 kb)

Supplementary Table 2

Association between the functional characterization of BRCA1/2 missense variants with LOH and signature 3. (XLSX 41 kb)

Supplementary Table 3

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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