Genetic Alterations during Colorectal-Tumor Development

TLDR

Because most colorectal carcinomas arise from adenomas, studying different stages of colorectal neoplasia can illuminate the genetic alterations involved in tumor progression. The study examined ras mutations and deletions of chromosomes 5, 17, and 18 in 172 colorectal tumor samples spanning early adenomas, adenomas with or without carcinoma foci, and carcinomas. RAS mutations were found in 58 % of adenomas >1 cm and 47 % of carcinomas but only 9 % of adenomas <1 cm, while deletions of chromosome 5 occurred in 29–35 % of adenomas and carcinomas (except in FAP adenomas), chromosome 18 was deleted in 73 % of carcinomas, 47 % of advanced adenomas, and 11–13 % of early adenomas, and chromosome 17p loss was seen in 75 % of carcinomas; these alterations accumulated stepwise, supporting a model in which oncogene activation and tumor suppressor loss drive colorectal tumorigenesis.

Abstract

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.