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.

Aberrant crypt foci as precursors in colorectal cancer progression

“…Genome-wide FAL rates do not significantly correlate with the smaller genomic events detected by ISSR-PCR and MSI, but loci on chromosomes 3,8,11,13,14,18, and 20 demonstrate significantly elevated instability by GII and/or FAL rate in LOHþ tumors [72]. A recent study from the same laboratory amplified 28 markers from microdissected tumors arising directly from villous adenomas and report a carcinoma mean FAL rate (0.135) significantly higher than that of the adjacent adenoma (0.052) [19]. The FAL rates reported for CRC and adenomas in this study were nearly twice that in their former study because the 28 markers chosen were already linked to LOH [19,72].…”

“…A recent study from the same laboratory amplified 28 markers from microdissected tumors arising directly from villous adenomas and report a carcinoma mean FAL rate (0.135) significantly higher than that of the adjacent adenoma (0.052) [19]. The FAL rates reported for CRC and adenomas in this study were nearly twice that in their former study because the 28 markers chosen were already linked to LOH [19,72]. These LOH markers in adenomas and CRC provide loci for further genetic profiling of ACF relative to tumor progression.…”

“…Patients with a greater number of adenomas have significantly more ACF, and these ACF tended to be larger (crypt/ focus) and dysplastic [3,18]. Interestingly, adenomas diagnosed during high-magnification chromoscopic colonoscopy (HMCC) have been observed with confluent margins to adjacent ACF [3], a phenomenon similar to carcinomas arising directly from adenomas in surgical specimens [19]. A greater ACF density (ACF/cm 2 ) is observed in resected colons with sporadic CRC than in those with benign disease such as diverticulitis [1,2,[20][21][22].…”

Rectal aberrant crypt foci (ACF) as a predictor of benign and malignant neoplastic lesions in the large intestine

“…Numerous studies have shown that individuals with adenomas and colorectal cancer (CRC) have a higher percentage of ACF as compared to patients without a similar pathology in the large intestine. It is important that in some studies ACF were found in the direct vicinity of adenomas as were adenomas found at the periphery of CRC [6,7]. An analysis of various studies shows that dysplastic ACF most commonly accompany adenomas and CRC [6].…”