title: Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel.
abstract: We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10-3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22-90) years and for ovarian cancer (n = 15) 54 (38-69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Yablonski-Peretz
authors.affiliation: The Oncology Institute Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Paluch-Shimon
authors.affiliation: Teva Pharmaceuticals, Shoham, Israel.
authors.forename: Lior Soussan
authors.initials: LS
authors.lastname: Gutman
authors.affiliation: Teva Pharmaceuticals, Shoham, Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kaplan
authors.affiliation: Teva Pharmaceuticals, Shoham, Israel.
authors.forename: Addie
authors.initials: A
authors.lastname: Dvir
authors.affiliation: Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Barnes-Kedar
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
authors.forename: Luna
authors.initials: L
authors.lastname: Kadouri
authors.affiliation: Department of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Semenisty
authors.affiliation: Oncology Institute, Kaplan Medical Center, Rehovot, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Efrat
authors.affiliation: Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Neiman
authors.affiliation: Teva Pharmaceuticals, Shoham, Israel.
authors.forename: Yafit
authors.initials: Y
authors.lastname: Glasser
authors.affiliation: The Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Michaelson-Cohen
authors.affiliation: The Institute of Gastroenterology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Katz
authors.affiliation: The Oncology Institute Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.affiliation: The Oncology Institute Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Golan
authors.affiliation: The Genetics Institute, Assaf Harofe Medical Center, Zerifin, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Reish
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Hubert
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Safra
authors.affiliation: The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Yaron
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. feitan@post.tau.ac.il.|The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Tel-Hashomer, Israel. feitan@post.tau.ac.il.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
mesh_terms: D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D008403:Mass Screening
keywords: Cancer susceptibility genes; Germline mutations; High-risk families; Multigene genotyping