4.6 Article

The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk

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NPJ BREAST CANCER
卷 3, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41523-017-0024-8

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资金

  1. Breast Cancer Research Foundation
  2. National Institutes of Health [CA176785, CA116167, CA192393, CA92049]
  3. City of Hope Clinical Cancer Genomics Community Research Network
  4. National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50CA116201]
  5. Abramson Cancer Center Core grant [CA016520, 3P30CA008748-4, CA178800]
  6. U.S. Dept of Defense [W81XWH-13-1-0338]
  7. American Society of Clinical Oncology
  8. Rooney Family Foundation
  9. Commonwealth of Pennsylvania
  10. Sharon Levine Corzine Cancer Research Fund
  11. Robert and Kate Niehaus Clinical Cancer Initiative
  12. Filomen M. D'Agostino Foundation
  13. Andrew Sabin Family Fund
  14. STOP CANCER
  15. Oxnard Foundation
  16. American Cancer Society
  17. Avon Foundation [02-2013-044]
  18. Basser Center for BRCA
  19. Morris and Horowitz Families Endowed Professorship
  20. [RC4CA153828]

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Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA1/2-negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European-Caucasian multi-institutional cohort. Case-control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high-risk (odds ratio >5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case-control analysis demonstrated associations with familial breast cancer for ATM, PALB2, and TP53 mutations (odds ratio >3.0, p<10(-4)), BARD1 mutations (odds ratio = 3.2, p= 0.012), and CHEK2 truncating mutations (odds ratio = 1.6, p= 0.041). Our results demonstrate that approximately 4.7% of BRCA1/2 negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified PALB2 and TP53 as high-risk, ATM and BARD1 as moderate risk, and CHEK2 truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case-control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes.

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