title: Inherited predisposition to breast cancer among African American women.
abstract: African Americans have a disproportionate burden of aggressive young-onset breast cancer. Genomic testing for inherited predisposition to breast cancer is increasingly common in clinical practice, but comprehensive mutation profiles remain unknown for most minority populations. We evaluated 289 patients who self-identified as African American with primary invasive breast cancer and with personal or family cancer history or tumor characteristics associated with high genetic risk for all classes of germline mutations in known breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach. Sixty-eight damaging germline mutations were identified in 65 (22 %, 95 % CI 18-28 %) of the 289 subjects. Proportions of patients with unequivocally damaging mutations in a breast cancer gene were 26 % (47/180; 95 % confident interval [CI] 20-33 %) of those with breast cancer diagnosis before age 45; 25 % (26/103; 95 % CI 17-35 %) of those with triple-negative breast cancer (TNBC); 29 % (45/156; 95 % CI 22-37 %) of those with a first or second degree relative with breast cancer before age 60 or with ovarian cancer; and 57 % (4/7; 95 % CI 18-90 %) of those with both breast and ovarian cancer. Of patients with mutations, 80 % (52/65) carried mutations in BRCA1 and BRCA2 genes and 20 % (13/65) carried mutations in PALB2, CHEK2, BARD1, ATM, PTEN, or TP53. The mutational allelic spectrum was highly heterogeneous, with 57 different mutations in 65 patients. Of patients meeting selection criteria other than family history (i.e., with young age at diagnosis or TNBC), 48 % (64/133) had very limited information about the history of cancer in previous generations of their families. Mutations in BRCA1 and BRCA2 or another breast cancer gene occur in one in four African American breast cancer patients with early onset disease, family history of breast or ovarian cancer, or TNBC. Each of these criteria defines patients who would benefit from genomic testing and novel therapies targeting DNA repair pathways.
authors.affiliation: Department of Medicine, Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Churpek
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Yonglan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zakiya
authors.initials: Z
authors.lastname: Moton
authors.forename: Anne M
authors.initials: AM
authors.lastname: Thornton
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Silvia
authors.initials: S
authors.lastname: Casadei
authors.forename: Amanda
authors.initials: A
authors.lastname: Watts
authors.forename: Barbara
authors.initials: B
authors.lastname: Neistadt
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Churpek
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Zvosec
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Qun
authors.initials: Q
authors.lastname: Niu
authors.forename: Rafael
authors.initials: R
authors.lastname: Marquez
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Fackenthal
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D017668:Age of Onset; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human