Special Reports and ReviewsThe genetic basis of colorectal cancer: Insights into critical pathways of tumorigenesis☆
Section snippets
The APC/β-catenin pathway
The clinical and hereditary features of the FAP syndrome implied the existence of a single gene that regulates the formation of adenomatous polyps, the precursor for most colorectal cancers. The identification of an interstitial deletion on chromosome 5q in a patient with the Gardner's variant of FAP combined with classical linkage analysis facilitated the positional cloning of the APC gene in 1991.6, 7 The 15-exon gene encodes a multifunctional 2843–amino acid protein of 310 kilodaltons that,
The DNA mismatch repair pathway
Identification of the genes responsible for the HNPCC syndrome has led to insights into a novel mechanism of tumorigenesis in colon cancer. Mutations in five different genes (hMSH2, hMSH6, hMLH1, hPMS1, and hPMS2) have now been associated with the syndrome.43 As many as 45%–70% of HNPCC families who meet the Amsterdam criteria have mutations in one of these genes, most frequently either hMSH2 or hMLH1.44, 45 Each of the five genes encodes a protein involved in DNA mismatch repair, a complex
The TGF-β/SMAD pathway
TGF-β and related family members mediate a wide variety of biological effects, the most characteristic being its potent inhibition of proliferation.77 TGF-β initiates its broad spectrum of cellular responses through binding to the type II TGF-β receptor (TGFβRII). Binding to TGFβRII recruits and activates the type I receptor through phosphorylation of specific serine and threonine residues; signaling to the nucleus is then mediated through the so-called SMAD proteins, which are phosphorylated
Additional genetic events in colorectal tumorigenesis
KRAS is mutated in approximately 50% of colorectal tumors, and alterations in this small GTP-binding protein almost uniformly occur as activating point mutations in codons 12, 13, and to a lesser extent, 61. Among their many functions, K-ras pathways transduce signals from extracellular growth factors to regulate progression through the cell cycle and proliferation.2, 3 KRAS mutations are associated with up-regulation of DNA methyltransferase, cyclin D1, and gastrin, all of which may be
Epigenetic mechanisms in colorectal tumorigenesis
The transformation of a normal colonic epithelial cell to a malignant clone is the consequence of a complicated program in which the inappropriate activation of some genes is accompanied by the specific inactivation of others. Tumorigenesis requires that this altered program is passed on to subsequent generations of cells. Thus far, this review has focused primarily on the specific alterations in gene sequence (i.e., mutations) that fulfill these criteria. However, epigenetic mechanisms,
Implications for clinical management
Dramatic insights into the genetic basis of colon cancer have been achieved. These advances will undoubtedly have many direct applications to clinical management of patients with colorectal cancer. The feasibility of K-ras and p53 molecular analysis of stool for the diagnosis of colon cancer has already been shown and awaits further refinement.120, 121 Germline testing for the FAP and HNPCC syndromes is now commercially available and plays a valuable role in the counseling of high-risk
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Address requests for reprints to: Daniel C. Chung, M.D., Gastrointestinal Unit, GRJ 825, Massachusetts General Hospital, Boston, Massachusetts 02114. e-mail: [email protected].