Identification of predictive factors for the occurrence of predisposing MLH1 and MSH2 germline mutations among Sardinian patients with colorectal carcinoma

Factors predictive of carrying MLH1 and MSH2 germline mutations in patients with colorectal cancer (CRC) are as yet unknown. The aim of this population-based study, was to further define the role of MLH1/ MSH2 mutations through an evaluation clinic program with 362 consecutive Sardinian CRC patients. Eight MLH1/ MSH2 germline mutations were detected in 21 (6%) patients. Examining family cancer history, MLH1/ MSH2 mutations were found in 14/48 (29.2%) probands from CRC families and, among them, in 10/13 (76.9%) families fulfilling the Amsterdam criteria. The patients with low familial recurrence (two CRCs in the family) presented a much lower frequency of MLH1/ MSH2 mutations (2/55; 3.6%). Significantly higher rates of MLH1/ MSH2 mutations were found in patients with age of onset ⩽45 years ( P = 0.012) or with ⩾3 affected family members ( P = 0.009). While no significant predictive value was found for the presence of endometrial cancer within the family, earlier age of diagnosis and/or familial CRC recurrence should be considered as strong predictors for the occurrence of MLH1/ MSH2 mutations, and therefore useful in recommending CRC patients for genetic testing.