title: Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals.
abstract: Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.
authors.affiliation: Laboratory of Genomics and Molecular Biology, Centro Internacional de Pesquisa e Ensino, A.C.Camargo Hospital, São Paulo, Brazil. mev_dv@yahoo.com
authors.forename: Mev Dominguez
authors.initials: MD
authors.lastname: Valentin
authors.forename: Felipe Carneiro
authors.initials: FC
authors.lastname: da Silva
authors.forename: Erika Maria Monteiro
authors.initials: EM
authors.lastname: dos Santos
authors.forename: Bianca Garcia
authors.initials: BG
authors.lastname: Lisboa
authors.forename: Ligia Petrolini
authors.initials: LP
authors.lastname: de Oliveira
authors.forename: Fabio de Oliveira
authors.initials: Fde O
authors.lastname: Ferreira
authors.forename: Israel
authors.initials: I
authors.lastname: Gomy
authors.forename: Wilson Toshihiko
authors.initials: WT
authors.lastname: Nakagawa
authors.forename: Samuel
authors.initials: S
authors.lastname: Aguiar Junior
authors.forename: Mariana
authors.initials: M
authors.lastname: Redal
authors.forename: Carlos
authors.initials: C
authors.lastname: Vaccaro
authors.forename: Adriana Della
authors.initials: AD
authors.lastname: Valle
authors.forename: Carlos
authors.initials: C
authors.lastname: Sarroca
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.forename: Benedito Mauro
authors.initials: BM
authors.lastname: Rossi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001118:Argentina; D001938:Brazil; D018389:Codon, Nonsense; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000208:ethnology / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014583:Uruguay
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein