Previous cytogenetic studies have indicated that a subset of large bowel adenomas have distal I p deletions. We addressed this question by examining 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 imbalance (Al) or loss of one allele (LOH) in 14 (20%). The locus most frequently changed was MSI, which maps t o lp33-35. Fluorescence in situ hybridisation with centromeric and telomeric probes for chromosome I, performed for I I polyps, did not yield an abnormal number of signals, in accordance with the interpretation that the observed Al and LOH were the result of interstitial deletions in Ip.
Whereas allelic imbalance at five other loci (mapping t o 5q, 8p, I Op, I I p and I7q) was found less frequently, and then mainly in large (>2 cm) tumours, the I p alterations were equally distributed among small (< I cm) and large polyps. They were preferentially found in left-side tumours. Instability at microsatellite loci-the mutator phenotype-is demonstrated by shifts in the electrophoretic mobility of normal alleles. The mutator phenotype was first associated with hereditary nonpolyposis colorectal cancer but is also 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 I2 dinucleotide repeat loci and found that seven tumours (six adenomas and one hyperplastic polyp) from seven patients had acquired new alleles not seen in the patients' corresponding normal DNA. Our results suggest that inactivation of a putative suppressor gene distally in chromosome arm I p is an early event in colorectal tumourigenesis. They also show that 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. Genes Chromosom Cancer 14: 182-188 (I 99.5).