title: A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy.
abstract: Germline mutations within the mismatch repair (MMR) genes are generally found in colorectal cancer (CRC) patients with a positive family history for the presence of the neoplasia. Clinical standard criteria have been established to define hereditary-non-polyposis-colorectal cancer (HNPCC)-prone families. Interestingly, the number of MMR gene mutations found in kindreds not fulfilling these criteria is still increasing. In this work we report the identification of a novel germline mutation of the hMSH2 gene, in two CRC-bearing subjects. The two probands belong to a large kindred from South Italy with no history suggestive for cancer aggregation. On the other hand, the early-onset of the neoplasia as well as the presence of a high number of tumor infiltrating lymphocytes (TILs) in the histological specimens of both patients, prompted us to perform a comprehensive genetic analysis. This analysis included the evaluation of the microsatellite instability (MSI) status with five markers according to the National Cancer Institute recommendations, followed by direct sequencing of the hMLH1 and hMSH2 genes. Both probands were found to carry a germline missense (277 C>T) mutation leading to the change (L93F) of an amino acid residue in a highly conserved domain of the MSH2 protein. This mutation is accompanied by the loss of expression of the hMSH2 gene in the tumor tissue. Our findings suggest that in the presence of the above-mentioned criteria it may be useful to perform a molecular analysis of the MMR genes, even if the pedigree does not show marked aggregation of cancers.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi 'Magna Graecia' di Catanzaro, Campus di Germaneto, 88100 Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Baudi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Fersini
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Rosa
authors.initials: R
authors.lastname: Terracciano
authors.forename: Francarlo
authors.initials: F
authors.lastname: Leone
authors.forename: Barbara
authors.initials: B
authors.lastname: Quaresima
authors.forename: Maria C
authors.initials: MC
authors.lastname: Faniello
authors.forename: Loredana
authors.initials: L
authors.lastname: De Paola
authors.forename: Patrizia
authors.initials: P
authors.lastname: Doldo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.forename: Francesco
authors.initials: F
authors.lastname: Costanzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Venuta
mesh_terms: D000328:Adult; D020137:Base Pair Mismatch; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008297:Male; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D020125:Mutation, Missense; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes