MOLECULAR-BIOLOGY OF COLORECTAL-CANCER

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the patholog ic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a p roliferative advantage to cells and contribute to development of the m alignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene - a tumor-suppressor gene o n chromosome 5q - mark one of the earliest events in colorectal carcin ogenesis. Germline mutation of the APC gene and subsequent somatic mut ation of the second APC allele cause the inherited familial adenomatou s polyposis syndrome. This syndrome is characterized by the presence o f hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to d ysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity o n the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict p oor prognosis. Loss of the 18q region is thought to contribute to inac tivation of the DCC tumor-suppressor gene. More recent evidence sugges ts that other tumor-suppressor genes - DPC4 and MADR2 of the transform ing growth factor beta (TGF-beta) pathway - also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-su ppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apopt osis. Neoplastic progression is probably accompanied by additional, un discovered genetic events, which are indicated by allelic loss on chro mosomes 1q, 4p, 6p, 8p, 9q, and 220 in 25% to 50% of colorectal cancer s. Recently, a third class of genes, DNA repair genes, has been implic ated in tumorigenesis of colorectal cancer. Study findings suggest tha t DNA mismatch repair deficiency, due to germline mutation of the hMSH 2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of heredit ary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display mi crosatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficie ncy may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulinlike growth-factor II receptor. Indivi duals from families at high risk for colorectal cancer (hereditary non polyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent st udies have examined colorectal carcinogenesis in the light of other ge netic processes. Telomerase activity is present in almost all cancers, including Colorectal cancer, but rarely in benign lesions such as ade nomatous polyps or normal tissues. Furthermore, genetic alterations th at allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In, addition, hypomethy lation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.