Rinat Bernstein-Molho1,2, Amihood Singer3, Yael Laitman4, Iris Netzer4, Shelley Zalmanoviz4, Eitan Friedman5,6. 1. Breast Cancer Center, Oncology Institute, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. 2. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 3. Community Genetics, Public Health Services, Ministry of Health, Jerusalem, Israel. 4. Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. 5. Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. eitan.friedman@sheba.health.gov.il. 6. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. eitan.friedman@sheba.health.gov.il.
Abstract
BACKGROUND: Studies assessing the contribution of non-BRCA1/2 gene mutations to inherited breast cancer (BC) predisposition consistently reported low (up to 4%) yield. The current study aimed at assessing the spectrum of non-BRCA mutations in unselected Israeli BC cases and the utility of BRCAPRO and Penn II models, as tools for prediction of detecting non-BRCA1/2 mutations in Israeli BC patients who tested negative for the predominant Jewish BRCA1/2 mutations. METHODS: All consecutive Jewish Israeli BC patients at the Sheba Medical center who tested negative for the predominant BRCA1/2 mutations and elected to perform multigene panel testing were included. For each patient probability of BRCA mutation detection was calculated by the Penn II algorithm and the BRCAPRO tool. RESULTS: Overall, 144 cases were included (median age at diagnosis was 48, range 20-73 years); 48% were Ashkenazim. One patient harbored a non-founder BRCA1 mutation (c.5434C>G; p.P1812A). Pathogenic/likely pathogenic (P/LP) mutations in non-BRCA1/2 genes were detected in additional 14/144 patients, including CHEK2 (n = 5), RAD51D (n = 2), MSH6 (n = 2), and one each in ATM, RET, TP53, NBN, and BAP1. Using a cutoff of 15% probability of BRCA mutation detection, both models accurately predicted the observed carrier rate of non-BRCA mutations. CONCLUSIONS: In unselected Jewish Israeli BC patients, the rate of detecting non-founder BRCA1/2 mutations is low, with CHEK2 mutations detected in 3.4% of cases. BRCA1/2 mutation prediction models may be utilized for selecting patients eligible for further multigene panel testing after exclusion of predominant BRCA1/2 mutations.
BACKGROUND: Studies assessing the contribution of non-BRCA1/2 gene mutations to inherited breast cancer (BC) predisposition consistently reported low (up to 4%) yield. The current study aimed at assessing the spectrum of non-BRCA mutations in unselected Israeli BC cases and the utility of BRCAPRO and Penn II models, as tools for prediction of detecting non-BRCA1/2 mutations in Israeli BC patients who tested negative for the predominant Jewish BRCA1/2 mutations. METHODS: All consecutive Jewish Israeli BC patients at the Sheba Medical center who tested negative for the predominant BRCA1/2 mutations and elected to perform multigene panel testing were included. For each patient probability of BRCA mutation detection was calculated by the Penn II algorithm and the BRCAPRO tool. RESULTS: Overall, 144 cases were included (median age at diagnosis was 48, range 20-73 years); 48% were Ashkenazim. One patient harbored a non-founder BRCA1 mutation (c.5434C>G; p.P1812A). Pathogenic/likely pathogenic (P/LP) mutations in non-BRCA1/2 genes were detected in additional 14/144 patients, including CHEK2 (n = 5), RAD51D (n = 2), MSH6 (n = 2), and one each in ATM, RET, TP53, NBN, and BAP1. Using a cutoff of 15% probability of BRCA mutation detection, both models accurately predicted the observed carrier rate of non-BRCA mutations. CONCLUSIONS: In unselected Jewish Israeli BC patients, the rate of detecting non-founder BRCA1/2 mutations is low, with CHEK2 mutations detected in 3.4% of cases. BRCA1/2 mutation prediction models may be utilized for selecting patients eligible for further multigene panel testing after exclusion of predominant BRCA1/2 mutations.
Entities:
Keywords:
Breast cancer; Cancer susceptibility genes; Non-BRCA1/2; Prediction models
Authors: Oliver Millan Catalan; Alma D Campos-Parra; Rafael Vázquez-Romo; David Cantú de León; Nadia Jacobo-Herrera; Fermín Morales-González; César López-Camarillo; Mauricio Rodríguez-Dorantes; Eduardo López-Urrutia; Carlos Pérez-Plasencia Journal: Cancers (Basel) Date: 2019-08-26 Impact factor: 6.639