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


Authors: Slavin, T. P.; Maxwell, K. N.; Lilyquist, J.; Vijai, J.; Neuhausen, S. L.; Hart, S. N.; Ravichandran, V.; Thomas, T.; Maria, A.; Villano, D.; Schrader, K. A.; Moore, R.; Hu, C.; Wubbenhorst, B.; Wenz, B. M.; D'Andrea, K.; Robson, M. E.; Peterlongo, P.; Bonanni, B.; Ford, J. M.; Garber, J. E.; Domchek, S. M.; Szabo, C.; Offit, K.; Nathanson, K. L.; Weitzel, J. N.; Couch, F. J.
Article Title: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk
Abstract: 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.
Keywords: genetics; population; genomics; medicine; brca2; frequency; carriers; germline mutations; ashkenazi jewish; copy-number variation
Journal Title: npj Breast Cancer
Volume: 3
ISSN: 2374-4677
Publisher: Nature Publishing Group  
Date Published: 2017-06-09
Start Page: 22
Language: English
ACCESSION: WOS:000411091900001
DOI: 10.1038/s41523-017-0024-8
PROVIDER: wos
PMCID: PMC5466608
PUBMED: 28649662
Notes: Corrigendum issued, see DOI: 10.1038/s41523-017-0046-2 -- Article -- Source: Wos
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MSK Authors
  1. Kenneth Offit
    494 Offit
  2. Mark E Robson
    358 Robson
  3. Vijai Joseph
    113 Joseph
  4. Tinu Mary Thomas
    15 Thomas
  5. Danylo Julian Villano
    13 Villano
  6. Ann   Maria
    7 Maria