Support for hMLH1 and MGMT silencing as a mechanism of tumorigenesis in the hyperplastic-adenoma-carcinoma (serrated) carcinogenic pathway in the colon.

BACKGROUND: Down-regulation of DNA repair genes has been proposed as an important mechanism of tumorigenesis in some colon cancers. This mechanism has also recently been implicated in the newly postulated hyperplastic polyp-serrated adenoma-carcinoma ("serrated") pathway of carcinogenesis, although this has never been investigated thoroughly. The aim of this study was to evaluate hMLH1, hMSH2, MGMT, as well as MIB-1, p53, and beta-catenin immunoexpression in an uncommon cohort of mixed colonic polyps that contain a combination of hyperplastic and adenomatous features (n = 21), and in some (n = 7), carcinoma as well.

DESIGN: The clinical, pathological, and immunophenotypic (hMLH1, hMSH2, MGMT, MIB-1, p53, and beta-catenin) properties of 28 mixed hyperplastic and adenomatous polyps of the colon (7 of which also contained carcinoma within the same lesion) were evaluated for the above immunopeptides in each of the different morphologic areas of the polyps, and the results were compared to traditional hyperplastic polyps, serrated adenomas, and conventional (nonserrated) adenomas.

RESULTS: Clinically, most mixed polyps with carcinoma occurred in the ascending colon (86%), and pathologically, the adenomatous component of most mixed polyps was serrated (96%). Mixed polyps, particularly those with carcinoma, showed loss of hMLH1 (33%), MGMT (37%), and even hMSH2 (11%) with significantly higher frequency compared to hyperplastic polyps, conventional adenomas, and serrated adenomas. More specifically, loss of hMLH1 and MGMT were more frequent in epithelium of higher neoplastic grade in mixed polyps. However, hMSH2 loss was only present in the adenoma component and never in the hyperplastic or carcinomatous areas of these polyps. Defects in MIB-1 proliferation indices and p53 were not significantly different among the same epithelial components in each of the polyp groups. However, conventional adenomas showed significantly higher rates of nuclear beta -catenin staining (100%) in comparison to the adenomatous component of mixed polyps (60%).

CONCLUSIONS: Loss of hMLH1 and MGMT play a prominent role in the serrated pathway of carcinogenesis in the colon.