title: Haplotypes of the I157T CHEK2 germline mutation in ethnically diverse populations.
abstract: The CHEK2*I157T missense mutation, reported in ethnically diverse, high-risk families, moderately increases breast and colon cancer risk. The present study assessed whether this mutation represents a founder mutation. Participants identified in high risk clinics or from consecutive cancer patients in Israel, Poland, Latvia, and Finland, were either carriers of the CHEK2*I157T mutation or non-carrier family members. Multi-locus genotyping employed two intragenic markers and five CHEK2 gene flanking markers, spanning about 645 kb. Haplotyping was done when families were available for phasing. Overall, 101 individuals (83 I157T*CHEK2 mutation carriers) were genotyped: 16 Finnish individuals from 11 families (14 mutation carriers, two non-carrier family members), 50 Polish individuals (20 families) (35 carriers, 15 non-carriers), 28 unrelated Latvian mutation carriers, and seven Israeli participants (two families) (six mutation carriers, one non-carrier). Overall 36/83 mutation carriers (43%) were diagnosed with breast cancer, 15/83 (18%)-colon cancer, three-ovarian cancer, one-thyroid cancer, and the rest (n = 28) were asymptomatic. A common core haplotype was detected in all I157T*CHEK2 mutation carriers of Israeli, Polish, and Finnish origin between markers D22S275-D22S689 (approximately 258 kb), with a different allele pattern in Latvians. In conclusion, CHEK2*I157T missense mutation is a founder mutation in ethnically diverse populations, but may also be a mutational hotspot.
authors.affiliation: Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.forename: Arvids
authors.initials: A
authors.lastname: Irmejs
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Janis
authors.initials: J
authors.lastname: Gardovskis
authors.forename: Edvins
authors.initials: E
authors.lastname: Miklasevics
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
mesh_terms: D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases