Microsatellite instability and mismatch-repair protein expression in hereditary and sporadic colorectal carcinogenesis

Aberrant crypt foci (ACF) are microscopic clusters of altered colonic crypt s considered premalignant lesions in the large bowel. Genomic instability a t short tandem repeats in the DNA, referred to as microsatellite instabilit y (MSI) is the hallmark of hereditary nonpolyposis colorectal carcinoma (HN PCC) caused by mutations in DNA mismatch-repair genes, mostly hMLH1 and LMS H2. In this study, we evaluated for MSI ACF (n = 16), adenomas (n = 18), ca rcinomas (n = 22), and lymph node metastases (n = 3) from 17 patients with colorectal cancer positive for MSI, Ten patients were members of HNPCC fami lies; 7 patients had no family history of cancer. MSI was found in 7 of 7 ( 100%) ACF and 11 of 12 (91%) adenomas from patients with HNPCC, MSI was not related to histology and size of ACF. A progressive increase in instabilit y as estimated by the number of shifted bands was observed along the ACF-ad enoma-carcinoma sequence, In contrast, two of nine (228) ACF and none of si x adenomas from patients with MSI sporadic carcinoma were unstable at micro satellite loci. hMLH1 or hMSH2 protein expression was altered only in MSI-p ositive premalignant lesions (ACF and/or adenomas), but not in all MSI-posi tive lesions in patients with HNPCC. These observations provide evidence of the premalignant nature of ACF in HNPCC and suggest that MSI is a very ear ly event both in HNPCC and in sporadic colorectal carcinogenesis, although in the latter it seems infrequent.