Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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.

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

“…Both CHEK2 and ATM are well-established breast cancer susceptibility genes with low to medium penetrance(42). Interestingly, CHEK2 germline variants specifically associate with increased incidence of ER + tumors(43), suggesting that the role of Chk2 in connecting ER to the cell cycle highlighted in our investigation is a fundamental pathway that contributes to development of luminal tumors.…”

The use of panel testing in familial breast and ovarian cancer

“…17 Similarly, one third (168/488) of women with breast cancer undergoing sequencing of 25 breast/ovarian cancer susceptibility genes harboured VUS, with as many as three variants found per patient. 18 Most VUS will likely turn out to be non-pathogenic, but until this is known they will remain a source of considerable anxiety for the patient and their family.…”

Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility

“…About 5-10 percent of cancers are considered hereditary and occur in individuals genetically predisposed to developing cancer (1). Inherited defects in DNA repair genes have been implicated in cancer susceptibility in colon (2), breast (3,4), and ovarian (5) cancers. Early identification of cancer-susceptible individuals can aid in risk stratification, screening, and prevention.…”