MOLECULAR NATURE OF COLON TUMORS IN HEREDITARY NONPOLYPOSIS COLON-CANCER, FAMILIAL POLYPOSIS, AND SPORADIC COLON-CANCER

Background & Aims: Microsatellite instability (replication error [RER] ) is a characteristic of tumors in hereditary nonpolyposis colon cance r (HNPCC), but the mechanism of HNPCC carcinogenesis is not yet unders tood. To clarify the nature of HNPCC tumors, RER and genetic changes w ere compared between HNPCC and non-HNPCC tumors. Methods: RER and gene tic changes were analyzed in 21 HNPCC, 389 familial adenomatous polypo sis, and 206 sporadic tumors using polymerase chain reaction, single-s trand conformation polymorphism, sequencing, and Southern hybridizatio n. Results: In HNPCC, 95% tumors at all stages showed RER positivity ( altered loci, 4.3 of 5). In familial adenomatous polyposis and sporadi c tumors, RER positivity (1.7 of 5) was 3% in adenoma and intramucosal carcinoma, 13%-24% in invasive carcinoma, and 35% in carcinoma metast asized to liver. Fifty percent of RER-positive HNPCC tumors had both g ermline and somatic mutations of hMSH2 or hMLH1 gene, whereas 6% of RE R-positive non-HNPCC had somatic mutation. APC, p53, and K-ras-2 mutat ions and loss of heterozygosity of tumor-suppressor genes were signifi cantly less frequent (P = 0.03 to 0.0006) but transforming growth fact or beta type II receptor mutation was significantly more frequent (P = 0.000001) in HNPCC than in non-HNPCC. Conclusions: RER positivity occ urs from an early stage of carcinogenesis in HNPCC but in later stages in non-HNPCC. Most HNPCC tumors may develop through different genetic changes from those in the adenoma-carcinoma sequence, although a cert ain percentage develops through APC mutation.