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Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer

✍ Scribed by Alessandra Viel; Maurizio Genuardi; Eugenia Capozzi; Francesca Leonardi; Alfonso Bellacosa; Maria Paravatou-Petsotas; Maria Grazia Pomponi; Mara Fornasarig; Antonio Percesepe; Luca Roncucci; Maria Grazia Tamassia; Piero Benatti; Maurizio Ponz de Leon; Agostino Valenti; Marcello Covino; Marcello Anti; Mirto Foletto; Mauro Boiocchi; Giovanni Neri

Publisher
John Wiley and Sons
Year
1997
Tongue
English
Weight
331 KB
Volume
18
Category
Article
ISSN
1045-2257

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✦ Synopsis

Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the 88Amsterdam criteria.'' A combination of different techniques, including reverse transcription-polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations.

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