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 sever al tumor types. In an effort to more precisely locate the putative tumor su ppressor gene(s) on chromosome 4 involved in the multistage pathogenesis of colorectal carcinomas, we performed loss of heterozygosity (LOH) studies u sing 19 polymorphic microsatellite markers. After precise microdissection o f archival surgical cases, we determined LOH in DNA obtained from 23 colore ctal adenocarcinomas, 20 colorectal adenomas, and from corresponding histol ogically normal-appearing colonic epithelial samples adjacent to the tumors and at the resection margins. We observed localized deletions of chromosom e 4 at multiple regions in both carcinomas and adenomas. We identified dele tions at 4 previously identified regions: R1 at 4q33-34 (18%-33%), R2 at 4q 25-26 (45%-65%), R3 at 4p15.1-15.3 (35%-47%), and R4 at 4q16.3 (40%-49%). S ix of fifteen (40%) cases examined with deletions of chromosome 4 in either adenocarcinomas or adenomas had loss of the same parental alleles in adjac ent histologically normal epithelium but not in epithelial samples from the surgical resection margins. The deletions, which commenced on the short ar m of chromosome 4 (regions R3 and/or R4), were more extensive in adenocarci nomas, intermediate in length in adenomas, and least extensive in histologi cally normal epithelium. Our results suggest that there may be multiple put ative tumor suppressor genes located on both arms of chromosome 4 whose ina ctivation are important early events in the pathogenesis of colorectal carc inoma. HUM PATHOL 32:169-177. Copyright (C) 2001 by W.B. Saunders Company.