Molecular Genetics of Colorectal Cancer: An Overview

Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality from cancers in the United States. Recent studies have revealed the paradigm in which sequential genetic changes (mutations) result in the progression from normal colonic tissues to frank carcinoma. In particular, the study of hereditary colorectal cancer and polyposis syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colon cancer has contributed enormously to the understanding of the pathogenesis of CRC. Here we describe some of the common genetic pathways in CRC and the mechanisms of action for some of the key genes involved in the formation of CRC. The understanding of the genetic pathways and functions in CRC may lead to the development of novel therapeutic approaches for treating this deadly disease.

Figure 1

. The genetic paradigm of colorectal cancer. The genetic changes that accompany the stepwise transformation of normal colonic mucosal tissues to carcinoma are depicted in the model. Both mutational inactivation of tumor suppressor genes (light shaded) and activation of oncogenes (dark shaded) are involved. The sequence of gene mutations in the APC pathway is shown on the top and those in the mismatch repair pathway is shown in the bottom. ACF—aberrant crypt foci; APC— adenomatous polyposis coli; COX-2—cyclooxygenase-2.

Figure 2

The Wnt/β-catenin signaling pathway. Readers are referred to the text for a detailed description of the pathway. βCat—β-catenin; CtBP—C-terminal binding protein; Dsh—disheveled; Fz—frizzled; Gro—Groucho; GSK—glycogen synthase kinase 3β; LRP—low-density lipoprotein receptor-related protein; TCF—T-cell factor.