Deletions of chromosome 4 occur early during the pathogenesis of colorectal carcinoma

Allelic losses at one or both arms of chromosome 4 are frequent in several tumor types, but information about colorectal carcinoma is limited. We have previously defined 4 nonoverlapping regions of frequent deletions in several tumor types. In an effort to more precisely locate the putative tumor suppressor gene(s) on chromosome 4 involved in the multistage pathogenesis of colorectal carcinomas, we performed loss of heterozygosity (LOH) studies using 19 polymorphic microsatellite markers. After precise microdissection of archival surgical cases, we determined LOH in DNA obtained from 23 colorectal adenocarcinomas, 20 colorectal adenomas, and from corresponding histologically normal-appearing colonic epithelial samples adjacent to the tumors and at the resection margins. We observed localized deletions of chromosome 4 at multiple regions in both carcinomas and adenomas. We identified deletions at 4 previously identified regions: R1 at 4q33-34 (18%-33%), R2 at 4q25-26 (45%-65%), R3 at 4p15.1-15.3 (35%-47%), and R4 at 4p16.3 (40%-49%). Six of fifteen (40%) cases examined with deletions of chromosome 4 in either adenocarcinomas or adenomas had loss of the same parental alleles in adjacent histologically normal epithelium but not in epithelial samples from the surgical resection margins. The deletions, which commenced on the short arm of chromosome 4 (regions R3 and/or R4), were more extensive in adenocarcinomas, intermediate in length in adenomas, and least extensive in histologically normal epithelium. Our results suggest that there may be multiple putative tumor suppressor genes located on both arms of chromosome 4 whose inactivation are important early events in the pathogenesis of colorectal carcinoma.