title: Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.
abstract: Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case–control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2–78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8–217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Raskin
authors.forename: F
authors.initials: F
authors.lastname: Schwenter
authors.forename: M
authors.initials: M
authors.lastname: Freytsis
authors.forename: M
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: N
authors.initials: N
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Chong
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
authors.forename: D A
authors.initials: DA
authors.lastname: Levine
authors.forename: F
authors.initials: F
authors.lastname: Bogomolniy
authors.forename: M
authors.initials: M
authors.lastname: Aronson
authors.forename: S N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: K S
authors.initials: KS
authors.lastname: Hunt
authors.forename: G
authors.initials: G
authors.lastname: Rennert
authors.forename: S
authors.initials: S
authors.lastname: Gallinger
authors.forename: S B
authors.initials: SB
authors.lastname: Gruber
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000208:ethnology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000208:ethnology / Q000235:genetics; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D007585:Jews; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D005819:Genetic Markers