Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features.
Experimental design: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations.
Results: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers.
Conclusions: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.