DELETION OF IP LOCI AND MICROSATELLITE INSTABILITY IN COLORECTAL POLYPS

Previous cytogenetic studies have indicated that a subset of large bow el adenomas have distal 1p deletions. We addressed this question by ex amining 70 sporadic polyps (63 adenomas, 5 hyperplastic polyps, and 2 polyps of undetermined histology) from 55 patients for alterations at eight loci on the short arm of chromosome I and found allelic imbalanc e (Al) or loss of one allele (LOH) in 14 (20%). The locus most frequen tly changed was MSI, which maps to 1p33-35. Fluorescence in situ hybri disation with centromeric and telomeric probes for chromosome 1, perfo rmed for 11 polyps, did not yield an abnormal number of signals, in ac cordance with the interpretation that the observed Al and LOH were the result of interstitial deletions in 1p. Whereas allelic imbalance at five other loci (mapping to 59, 8p, 10p, 11p and 17q) was found less f requently, and then mainly in large (>2 cm) tumours, the 1p alteration s were equally distributed among small (<1 cm) and large polyps. They were preferentially found in left-side tumours. Instability at microsa tellite loci-the mutator phenotype-is demonstrated by shifts in the el ectrophoretic mobility of normal alleles. The mutator phenotype was fi rst associated with hereditary nonpolyposis colorectal cancer but is a lso occasionally found in sporadic colorectal carcinomas; however, it is still uncertain when in the adenoma-carcinoma sequence in this type of genomic instability arises. We therefore looked for it at 12 dinuc leotide repeat loci and found that seven rumours (six adenomas and one hyperplastic polyp) from seven patients had acquired new alleles not seen in the patients' corresponding normal DNA. Our results suggest th at inactivation of a putative suppressor gene distally in chromosome a rm 1p is an early event in colorectal tumourigenesis. They also show t hat microsatellite instability can be detected in large bowel polyps, indicating that this phenomenon, too, probably plays a pathogenic role for some colorectal tumours early in the adenoma-carcinoma sequence. (C) 1995 Wiley-Liss, Inc.