GENETIC INSTABILITY ASSOCIATED WITH ADENOMA TO CARCINOMA PROGRESSION IN HEREDITARY NONPOLYPOSIS COLON-CANCER

Background & Aims: Genetic instability related to defective DNA mismat ch repair genes may be involved in the pathogenesis of carcinoma in he reditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tis sues from patients inheriting defects in human MSH2 or human MLH1 do n ot show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma st age promotes malignant transformation by studying adenoma-carcinoma pr ogression in HNPCC. Methods: Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinom a stages from formalin-fixed paraffin-embedded HNPCC tumors. Results: Although genetic instability was observed at some loci in almost all c ases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign are as of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neop lastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. Conclusions: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic in stability are more likely to progress to carcinoma. Topographic genoty ping data provides evidence supporting the hypothesis of adenoma-carci noma progression in HNPCC.