title: New founding mutation in MSH2 associated with hereditary nonpolyposis colorectal cancer syndrome on the Island of Tenerife.
abstract: Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary syndrome with genetic heterogeneity. The disease is caused by mutations or epigenetic silencing in DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2 and MLH3, although the vast majority of cases correspond to mutations of MLH1 and MSH2. We herein describe a nucleotide change, c.2063T>G in exon 13 of the MSH2 gene, present in families that fulfill the Amsterdam criteria for Lynch syndrome and originate from northern Tenerife (Canary Islands-Spain). This mutation is expected to result in a nonconservative amino acid change, M688R, at the ATPase domain of the MSH2 protein. We found five large families with this mutation, and about half the individuals heterozygous for M688R developed malignancies by the sixth decade of life. In many cases analyzed, their tumors revealed loss of the normal allele, being homozygous for M688R. There is an evidence of historical isolation for the population studied, which could have favored a considerable genetic drift. The presence of the same mutation and the disease associated-haplotype conservation in families not directly related can be probably the consequence of a bottleneck in the founding of this population (rather than a relatively recent founding of the mutation).
authors.affiliation: Servicio de Cirugía General y Digestiva, Hospital Universitario de Canarias, Ofra-La Cuesta 38071 La Laguna, Tenerife, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Medina-Arana
authors.forename: Ysamar
authors.initials: Y
authors.lastname: Barrios
authors.forename: Antonia
authors.initials: A
authors.lastname: Fernández-Peralta
authors.forename: Mercedes
authors.initials: M
authors.lastname: Herrera
authors.forename: Nancy
authors.initials: N
authors.lastname: Chinea
authors.forename: Nieves
authors.initials: N
authors.lastname: Lorenzo
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jiménez
authors.forename: Juana Victoria
authors.initials: JV
authors.lastname: Martín-López
authors.forename: Fernando
authors.initials: F
authors.lastname: González-Hermoso
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.forename: Juan J
authors.initials: JJ
authors.lastname: González-Aguilera
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013030:Spain
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein