title: Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome.
abstract: Lynch syndrome (LS) accounts for 3-5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Felipe
authors.initials: F
authors.lastname: Carneiro da Silva
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: José Roberto de Oliveira
authors.initials: JR
authors.lastname: Ferreira
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Giovana Tardin
authors.initials: GT
authors.lastname: Torrezan
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Márcia Cristina Pena
authors.initials: MC
authors.lastname: Figueiredo
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Érika Maria Monteiro
authors.initials: ÉM
authors.lastname: Santos
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Wilson Toshihiko
authors.initials: WT
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Rafael Canfield
authors.initials: RC
authors.lastname: Brianese
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Ligia
authors.initials: L
authors.lastname: Petrolini de Oliveira
authors.affiliation: Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Maria Dirlei
authors.initials: MD
authors.lastname: Begnani
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aguiar-Junior
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Benedito Mauro
authors.initials: BM
authors.lastname: Rossi
authors.affiliation: Department of Colorectal Tumors, A. C. Camargo Cancer Center, São Paulo, Brazil.
authors.forename: Fábio de Oliveira
authors.initials: Fde O
authors.lastname: Ferreira
authors.affiliation: Laboratory of Genomics and Molecular Biology, International Research Center/CIPE-A. C. Camargo Cancer Center, São Paulo, Brazil; National Institute of Science and Technology in Oncogenomics (INCITO), Brazil.
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001938:Brazil; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D056915:DNA Copy Number Variations; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D009363:Neoplasm Proteins; C088996:PMS1 protein, human; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070956:MutL Proteins; D045643:DNA Repair Enzymes