Abstract
Colorectal cancer is the third most common cause of cancer-related death in both men and women in the western hemisphere. According to the American Cancer Society, an estimated 105,500 new cases of colon cancer with 57,100 deaths will occur in the U.S. in 2003, accounting for about 10% of cancer deaths. Among the colon cancer patients, hereditary risk contributes approximately 20%. The main inherited colorectal cancers are the familial adenomatous polyposis (FAP) and the hereditary nonpolyposis colorectal cancers (HNPCC). The FAP and HNPCC are caused due to mutations in the adenomatous polyposis coli (APC) and DNA mismatch repair (MMR) genes. The focus of this review is to summarize the functions of APC and MMR gene products in the development of colorectal cancers.
Highlights
Prognosis of colorectal cancer depends on the stage of the tumor at the time of diagnosis, with surgery being the most effective treatment
The focus of this review is to summarize the functions of adenomatous polyposis coli (APC) and mismatch repair (MMR) gene products in the development of colorectal cancers
The heterogeneous pattern of tumor mutations found in this study suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors
Summary
Prognosis of colorectal cancer depends on the stage of the tumor at the time of diagnosis, with surgery being the most effective treatment. Genes which are mutated at different stages of colorectal cancer development include tumor suppressor genes, protooncogenes, DNA repair genes, growth factors and their receptor genes, cell cycle checkpoint genes, and apoptosisrelated genes (Fig. 1). The β-catenin/Tcf complex regulates the protooncogene and cell cycle regulator c-myc [48], the G1/S-regulating cyclin D1 [49], the gene encoding the matrixdegrading metalloproteinase, matrysin [50], the AP-1 transcription factors c-jun and fra-1; and the urokinase-type plasminogen activator receptor gene [51] From this discussion, it is clear that the inactivation of APC causes activation of β-catenin, which results in the constitutive activation of Tcf/Lef response genes. This sequestration may account for the ability of c-Myc overexpression to substitute for p16 deficiency as noted in mouse fibroblast transformation [53] These studies establish a link among APC gene mutation, β-catenin stabilization, c-myc gene activation, and Cdk4/cyclin D1/ pRB/p16 pathway in colorectal cancer development.
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