Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women

Julie R. Palmer, ScD; Eric C. Polley, PhD; Chunling Hu, MD; Esther M. John, PhD; Christopher Haiman, ScD; Steven N. Hart, PhD; Mia Gaudet, PhD; Tuya Pal, MD; Hoda Anton-Culver, PhD; Amy Trentham-Dietz, PhD; Leslie Bernstein, PhD; Christine B. Ambrosone, PhD; Elisa V. Bandera, PhD; Kimberly A. Bertrand, ScD; Traci N. Bethea, PhD; Chi Gao, MSc; Rohan D. Gnanaolivu, MS; Hongyan Huang, PhD; Kun Y. Lee, PhD; Loic LeMarchand, MD; Jie Na, MS; Dale P. Sandler, PhD; Payal D. Shah, PhD; Siddhartha Yadav, MBBS; William Yang, BS; Jeffrey N. Weitzel, MD; Susan M. Domchek, MD; David E. Goldgar, PhD; Katherine L. Nathanson, MD; Peter Kraft, ScD; Song Yao, PhD; Fergus J. Couch, PhD


J Natl Cancer Inst. 2020;112(12):1213-1221. 

In This Article

Abstract and Introduction


Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.

Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.

Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.

Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.


In recent years, there have been notable advances in knowledge of both prevalence and penetrance of germline inactivating mutations in genes that are associated with a moderate (relative risk 2–4) or high (relative risk >4) risk of breast cancer.[1,2] In addition to BRCA1 and BRCA2,[3] at least 10 other genes [ATM,[4,5]BARD1,[6,7]CDH1,[8]CHEK2,[9]NF1,[10]PALB2,[11,12]PTEN,[13]RAD51C,[14]RAD51D,[15] and TP53[16]] have been associated with moderate or high risk of breast cancer in women of European ancestry (EA). This information has been used to inform cancer risk management such as prophylactic surgery or enhanced screening and is increasingly being used to guide targeted treatments.

However, limited data are available from women of African ancestry, including from African American (AA) women, who have a higher incidence of breast cancer at young ages, a higher incidence of estrogen receptor (ER)-negative breast cancer, and a 42% higher breast cancer mortality rate than non-Hispanic white women.[17,18] A recent study of African ancestry women reported relative risks for BRCA1 and BRCA2 only.[19] Stable estimates of the prevalence of pathogenic mutations in AA women and the magnitude of associations between mutations and breast cancer risk are not available, despite being critical for informing appropriate recommendations for genetic testing and for counseling on preventive strategies. To fill these critical gaps, we assembled 5054 AA women with breast cancer and 4993 unaffected AA women from 10 epidemiologic studies and conducted uniform targeted multigene panel testing.