title: Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.
abstract: We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, The Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada; Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Castellsagué
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Volenik
authors.forename: S
authors.initials: S
authors.lastname: Giroux
authors.forename: R
authors.initials: R
authors.lastname: Gagné
authors.forename: B
authors.initials: B
authors.lastname: Maranda
authors.forename: A
authors.initials: A
authors.lastname: Roussel-Jobin
authors.forename: J
authors.initials: J
authors.lastname: Latreille
authors.forename: R
authors.initials: R
authors.lastname: Laframboise
authors.forename: L
authors.initials: L
authors.lastname: Palma
authors.forename: L
authors.initials: L
authors.lastname: Kasprzak
authors.forename: V A
authors.initials: VA
authors.lastname: Marcus
authors.forename: M
authors.initials: M
authors.lastname: Breguet
authors.forename: S
authors.initials: S
authors.lastname: Nolet
authors.forename: Z
authors.initials: Z
authors.lastname: El-Haffaf
authors.forename: K
authors.initials: K
authors.lastname: Australie
authors.forename: A
authors.initials: A
authors.lastname: Gologan
authors.forename: O
authors.initials: O
authors.lastname: Aleynikova
authors.forename: K
authors.initials: K
authors.lastname: Oros-Klein
authors.forename: C
authors.initials: C
authors.lastname: Greenwood
authors.forename: A M
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: D
authors.initials: D
authors.lastname: Provencher
authors.forename: M
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: G
authors.initials: G
authors.lastname: Chong
authors.forename: F
authors.initials: F
authors.lastname: Rousseau
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002170:Canada / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005190:Family; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011792:Quebec; D012306:Risk; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein
keywords: French Canadians; Lynch syndrome; MSH6; colorectal cancer; endometrial cancer; founder mutations; molecular diagnostics