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MLH1 and MSH2 constitutinal mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer

✍ Scribed by Maurizio Genuardi; Marcello Anti; Eugenia Capozzi; Francesca Leonardi; Mara Fornasarig; Elisabetta Novella; Alfonso Bellacosa; Agostino Valenti; Giovanni Battista Gasbarrini; Luca Roncucci; Piero Benatti; Antonio Percesepe; Maurizio Ponz de Leòn; Claudio Coco; Antonio de Paoli; Maurizio Valentini; Mauro Boiocchi; Giovanni Neri; Alessandra Viel

Publisher
John Wiley and Sons
Year
1998
Tongue
French
Weight
67 KB
Volume
75
Category
Article
ISSN
0020-7136

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✦ Synopsis

Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC

) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (F40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.

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