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

Abstract

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.

Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing

“…The mutant genes included BRCA1 published literature with germline sequencing data of large sample size. Therefore, we compared six frequently mutated genes between our Chinese cohort with published Caucasian 34 and African-American 35 cohorts. Comparing results are showed in Supplementary Fig.…”

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

“…However, this correlation was not confirmed in subsequent studies [ 90 ]. More recently, mutations in RECQL emerged as a moderate risk factor for BC in a cohort of African American women, indicating that mutations in the RECQL gene confer a moderate risk of BC [ 91 ]. These conflicting correlations could be explained by penetrance variability due to the consequences of the different types of the identified variants on the protein function and to the investigated cohorts belonging to different ethnicities [ 92 ].…”

Molecular and Cellular Factors Associated with Racial Disparity in Breast Cancer

“…Some BRCA1 and BRCA2 mutations that are inherited increase breast cancer risk in women. Together, mutations in the BRCA1 and BRCA2 genes contribute to about 20–25% of inherited breast cancers [ 107 ]. In addition, genetic testing of breast cancer patients revealed that the population which is of African or Bahaman decent showed higher frequencies of BRCA1 and BRCA2 mutations [ 108 ].…”

“…In addition, genetic testing of breast cancer patients revealed that the population which is of African or Bahaman decent showed higher frequencies of BRCA1 and BRCA2 mutations [ 108 ]. AA women carrying mutations in the PALB2, RAD51C, and RAD51D genes are more susceptible to ER-negative breast cancer [ 107 ]. Like BRCA1 and BRCA2 gene mutations, PALB2 mutations are also associated with high risk of breast cancer.…”

“…Mutations in the CHEK2, ATM, ERCC3 , and FANCC genes are linked to a moderate risk of ER-positive breast cancer. RECQL gene mutations present a moderate risk of all types of cancer [ 107 ]. Both CHK1 and CHK2 have important functions in cell cycle regulation, and have been found to be mutated more frequently in AA breast cancer patients [ 114 ].…”