title: Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.
abstract: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population.
  
  
  
  Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations.
  
  
  
  Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes.
  
  
  
  Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT. ntung@bidmc.harvard.edu.
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: John
authors.initials: J
authors.lastname: Kidd
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Allen
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Nanda
authors.initials: N
authors.lastname: Singh
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Nadine Tung, Beth Israel Deaconess Medical Center; Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Dana-Farber Cancer Institute; Nadine Tung, Nancy U. Lin, Eric P. Winer, and Judy E. Garber, Harvard Medical School, Boston, MA; and John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, and Anne-Renee Hartman, Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007585:Jews / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D064726:Triple Negative Breast Neoplasms / Q000235:genetics