title: Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.
authors.affiliation: Uruguayan Collaborative Group: Survey of Hereditary Oncologic Disorders, Hospital Central de las Fuerzas Armadas, 11600 Montevideo, Uruguay.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sarroca
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Nora
authors.initials: N
authors.lastname: Alfano
authors.forename: Gladys
authors.initials: G
authors.lastname: Tedesco
authors.forename: Adriana
authors.initials: A
authors.lastname: Della Valle
authors.forename: Alejandra
authors.initials: A
authors.lastname: Dominguez
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins; D018389:Codon, Nonsense; D003113:Colonoscopy; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D016368:Frameshift Mutation; D005817:Genetic Counseling; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014583:Uruguay
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein