Allelic losses at genomic instability-associated loci in villous adenomas and adjacent colorectal cancers

Abstract

Allelic imbalances in premalignant villous adenomas were compared with those in adjacent microdissected colorectal carcinoma that had arisen directly from the adenomas. Carcinoma-adenoma pairs were examined from 17 patients who underwent resections for colorectal cancer. In all, 28 microsatellite markers were examined, from regions of the genome where individual allelic losses have been associated with overall genomic instability in colorectal carcinomas. Microsatellite instability (MSI) was also evaluated for each marker in each tissue type. Loss of heterozygosity for multiple markers was found in 35% of adenomas and 65% of carcinomas; the average fractional allelic loss rate was 2.5 times higher in carcinomas than in adenomas. Of the 17 patients, 4 had MSI for >30% of markers in both adenoma and carcinoma, with no significant differences between the two tissues. Markers with particularly high imbalance rates in adenomas were seen on chromosomes 11, 14, and 15. These findings provide further evidence that genomic instability is an ongoing process during carcinogenesis, with a markedly increased frequency of allelic losses seen in carcinomas, compared with adjacent adenomas. Markers on chromosomes 11, 14, and 15 may become valuable tools in the identification of patients destined to progress to colorectal carcinomas.

Figure 1

Examples of autoradiographs of polyacrylamide gels of PCR amplification products using microsatellite markers and demonstrating loss of heterozygosity (LOH) and microsatellite instability (MSI) in villous adenomas. Left lane in each example represents normal mucosa with two normal alleles and right lane represents adenoma. Arrow for LOH shows loss of allele in adenoma, while arrow for MSI marks extra band representative of microsatellite instability.

Figure 2

Comparison of fractional allelic loss rate in adenomas and carcinomas for all informative markers each of the 17 patients. X-axis represents FAL rate calculated as described in the methods section. Y-axis lists patient number. Black bars represent carcinomas, while striped bars represent adenomas.

Figure 3

Comparison of fractional microsatellite instability rate in adenomas and carcinomas for all informative markers in each of the 17 patients. X-axis represents FINST rate calculated as described in the methods section. Y-axis lists patient number. Black bars represent carcinomas, while striped bars represent adenomas.

Figure 4

Comparison of fractional allelic loss rate in adenomas and carcinomas for each of the 28 microsatellite markers in all 17 patients. X-axis represents FAL rate calculated as described in the methods section. Y-axis lists marker number. Black bars represent carcinomas, while striped bars represent adenomas.