title: Lynch Syndrome in high risk Ashkenazi Jews in Israel.
abstract: Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Kyriat Hadassah, POB 12000, 91120, Jerusalem, Israel, yaelg@hadassah.org.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldberg
authors.forename: Inbal
authors.initials: I
authors.lastname: Kedar
authors.forename: Revital
authors.initials: R
authors.lastname: Kariiv
authors.forename: Naama
authors.initials: N
authors.lastname: Halpern
authors.forename: Morasha
authors.initials: M
authors.lastname: Plesser
authors.forename: Ayala
authors.initials: A
authors.lastname: Hubert
authors.forename: Luna
authors.initials: L
authors.lastname: Kaduri
authors.forename: Michal
authors.initials: M
authors.lastname: Sagi
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.forename: Dvorah
authors.initials: D
authors.lastname: Abeliovich
authors.forename: Tamar
authors.initials: T
authors.lastname: Hamburger
authors.forename: Aviram
authors.initials: A
authors.lastname: Nissan
authors.forename: Hanoch
authors.initials: H
authors.lastname: Goldshmidt
authors.forename: Irit
authors.initials: I
authors.lastname: Solar
authors.forename: Ravit
authors.initials: R
authors.lastname: Geva
authors.forename: Hana
authors.initials: H
authors.lastname: Strul
authors.forename: Guy
authors.initials: G
authors.lastname: Rosner
authors.forename: Hagit
authors.initials: H
authors.lastname: Baris
authors.forename: Zohar
authors.initials: Z
authors.lastname: Levi
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein