Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

Abstract

Importance Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined. Objective To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. Design, Setting, and Participants A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016. Main Outcomes and Measures Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes. Results The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks ofbreast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MREHA, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer. Conclusions and Relevance This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls

“…In this study, germ-line genetic testing results were evaluated for 19 OC susceptibility genes. All variants identified were evaluated by a five-tier variant classification system by Ambry Genetics as previously described [20]. In primary analyses, we included variants classified as pathogenic or likely pathogenic (Supplemental Table 7).…”

“…As previously shown in ovarian [12], breast [20] and prostate [21] cancer studies, the Exome Aggregation Consortium [22] (ExAC) dataset is an effective control dataset for the estimation of the gene-specific frequencies of pathogenic alterations. In this study OC cases were compared to non-Finnish European (NFE) controls from the ExAC dataset.…”

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

“…Cancer predisposition gene testing is useful for identifying individuals who may benefit from screening, prevention, and early detection of breast, ovarian, and colorectal cancer 1,2 and may be beneficial for individuals at risk of pancreatic cancer. 3,4 Family members of those with germline predisposition gene mutations may also benefit from enhanced cancer screening and prevention strategies.…”

“…1,13,14 DNA for panel testing was obtained from a series of 3030 patients with pancreatic cancer from a Mayo Clinic pancreas cancer registry, and DNA sequence data for the same predisposition genes were obtained from publicly available Genome Aggregation Database (gnomAD) and Exome Aggregation Consortium (ExAC) reference control groups. 15,16 Associations between mutations in each gene and pancreatic cancer were evaluated to establish a defined subset of genes that confer susceptibility to pancreatic cancer.…”

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population‐based study

“…[27][28][29][30][31][32][33][34][35] Briefly, methylation-specific polymerase chain reaction (PCR) was used to determine promoter methylation of the BRCA1, ER, and PR genes. [27][28][29][30][31][32][33][34][35] Briefly, methylation-specific polymerase chain reaction (PCR) was used to determine promoter methylation of the BRCA1, ER, and PR genes.…”