Allelic imbalance and cytogenetic deletion of 1p in colorectal adenomas: a target region identified between DIS199 and DIS234

Abstract

Both cytogenetic and molecular genetic analyses have shown that many colorectal adenomas carry an acquired deletion distally in the short arm of one chromosome 1, but the two methods have never been brought to bear on the same tumors. The major part of this study was the analysis of 53 previously short-term cultured and karyotyped colorectal adenomas for allelic imbalance at eight microsatellite loci in 1p. Allelic imbalances were detected in seven of the 12 adenomas that had cytogenetically visible abnormalities of chromosome 1, as well as in four adenomas that either had a normal karyotype (one case) or had clonal chromosome abnormalities that did not seem to involve chromosome 1 (three cases); i.e., 30% of the adenomas had abnormalities involving 1p by the combined approach. A minimal region of overlap seemed to map to between DIS199 and DIS234, suggesting that this is a relevant target region. This genomic area contains the human homologue of the tumor modifier gene Mom1 (1p35-36.1), which, in mice, modifies the number of intestinal tumors in multiple intestinal neoplasia (Min)-mutated animals. To evaluate whether the imbalances corresponded to interstitial deletions of 1p material, we performed fluorescence in situ hybridization with a pericentromeric probe (15 adenomas) and a telomeric probe (6 adenomas) on uncultured cells from the 16 adenomas with chromosome 1 abnormalities. Except for three adenomas that had already been shown by banding analysis to have a trisomic pattern, two centromere 1 signals were invariably found. In the cases hybridized with the 1p-telomeric probe, we found the same frequencies of telomeric and centromeric signals, in agreement with the interpretation that the deletions were interstitial. One of the 53 adenomas had genomic instability, seen as new alleles at five of eight microsatellite loci. A comparison of the genetic findings with clinicopathologic data indicated that adenomas in the rectum have 1p abnormalities more often than do adenomas of the sigmoid colon, and that adenomas with 1p changes are larger than adenomas without abnormalities of chromosome 1.