Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next‐generation sequencing with a 25‐gene panel

Abstract

BACKGROUND: Next-generation sequencing (NGS) allows for simultaneous sequencing of multiple cancer susceptibility genes and, for an individual, may be more efficient and less expensive than sequential testing. The authors assessed the frequency of deleterious germline mutations among individuals with breast cancer who were referred for BRCA1 and BRCA2 (BRCA1/2) gene testing using a panel of 25 genes associated with inherited cancer predisposition. METHODS: This was a cross-sectional study using NGS in 2158 individuals, including 1781 who were referred for commercial BRCA1/2 gene testing (cohort 1) and 377 who had detailed personal and family history and had previously tested negative for BRCA1/2 mutations (cohort 2). RESULTS: Mutations were identified in 16 genes, most frequently in BRCA1, BRCA2, CHEK2, ATM, and PALB2. Among the participants in cohort 1, 9.3% carried a BRCA1/2 mutation, 3.9% carried a mutation in another breast/ovarian cancer susceptibility gene, and 0.3% carried an incidental mutation in another cancer susceptibility gene unrelated to breast or ovarian cancer. In cohort 2, the frequency of mutations in breast/ovarian-associated genes other than BRCA1/2 was 2.9%, and an additional 0.8% had an incidental mutation. In cohort 1, Lynch syndrome-related mutations were identified in 7 individuals. In contrast to BRCA1/2 mutations, neither age at breast cancer diagnosis nor family history of ovarian or young breast cancer predicted for other mutations. The frequency of mutations in genes other than BRCA1/2 was lower in Ashkenazi Jews compared with non-Ashkenazi individuals (P5.026). CONCLUSIONS: Using an NGS 25-gene panel, the frequency of mutations in genes other than BRCA1/2 was 4.3%, and most mutations (3.9%) were identified in genes associated with breast/ovarian cancer. Cancer 2015;121:25-33. V C 2014 American Cancer Society.KEYWORDS: high-throughput nucleotide sequencing, breast neoplasms, genetic testing, BRCA1, BRCA2. INTRODUCTIONBreast cancer is expected to cause 40,000 deaths in the United States in 2014.1 This constitutes 7% of annual cancer deaths in the United States and underscores the importance of identifying at-risk individuals for prevention, early detection, and treatment. At least 10% of breast cancers occur in individuals who have germline mutations in highpenetrance or moderate-penetrance cancer susceptibility genes, which carry a relative cancer risk of >5-fold and 2-fold to 5-fold, respectively.2 Mutations in the early onset breast cancer genes BRCA1 and BRCA2 (BRCA1/2) are responsible for up to half of the heritable mutations in breast cancer. Although germline mutations in other recognized breast cancer susceptibility genes have been identified (eg, ataxia

Development and validation of a variant detection workflow for BRCA1 and BRCA2 genes and its clinical application based on the Ion Torrent technology

“…To overcome the technical challenges in terms of efficiency and turnaround time, the use of next-generation sequencing techniques have been adopted by diagnostic laboratories worldwide [9][10][11]. Here, we evaluated the performance of a panel for detecting BRCA1 and BRCA2 mutations, using the Ion Torrent PGM platform (Life Technologies) in a customized workflow.…”

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

“…In the last 2 years, the literature assessing the contribution of multigene panel testing in cohorts of patients with HBOC has grown. The results have been consistent even though the inclusion criteria sometimes differ [17][18][19][20][21][22][23][24][25][26][27][28][29][30]. The next challenge is to determine the consequences of these results on clinical management [NCCN clinical practice Guidelines-see URL].…”

Is it time to split strategies to treat homologous recombinant deficiency in pancreas cancer?

“…However, prevalence of individual mutations is low, comparable to observations in other cancer types (59)(60)(61). The low prevalence of these mutations and the relative rarity of pancreatic adenocarcinoma also render it challenging to delineate the penetrance strength of these mutations or their absolute risk in pancreatic carcinogenesis (with the exception of Roger and colleagues' effort on FANCC and FANCG).…”