Molecular Genetics of Colorectal Cancer


Cancer is a disorder of cellular growth and differentiation that is due to a loss of function of regulatory pathways and feedback loops. Colorectal cancer is an excellent example of this mechanism because access via colonoscopy to the spectrum of premalignant lesions in the colon and rectum allows demonstration and study of the process. Sporadic colorectal cancer arises from pre-existing benign lesions that begin small and gradually enlarge as they transition histologically and biologically toward cancer via an adenoma-carcinoma or a serrated polyp-carcinoma sequence. In 1988, Bert Vogelstein published a sequence of genetic abnormalities that appeared to correlate with the histologic adenoma to carcinoma sequence. Subsequent research has confirmed Vogelstein’s observations and has expanded knowledge and understanding of the genetics of colorectal carcinogenesis. It is now known that at least three different genetic mechanisms lead to colorectal cancer, producing cancers of different biology. Understanding the molecular genetics of colorectal neoplasia is important. Fostering an understanding of the molecular genetics of colorectal neoplasia is the purpose of this chapter.

Growth Control

Normal cell growth is regulated tightly by multiple redundant systems that are conserved from one species to another. Multiple dysfunctional genetic events need to accumulate in an epithelium before clinical effects of growth deregulation are noticeable. Each colorectal cancer is genetically unique and has accumulated mutations in an average of 90 different genes. Only a small number of these mutations are driver mutations, which are responsible for the carcinogenesis. Most are “passenger” mutations.

Normal cell growth is a balance between proteins that stimulate (coded for by proto-oncogenes) and proteins that inhibit (coded for by tumor suppressor genes). When that balance is disturbed, carcinogenesis can occur. Tumor suppressor genes and proto-oncogenes are organized into various signal transduction pathways that react to extracellular signals and transmit them to the cell nucleus, where an appropriate response is generated. Four main signal transduction pathways are involved in colorectal adenocarcinoma: wnt/wingless, epidermal growth factor (EGF), transforming growth factor (TGF)-β, and p53-mediated cell cycle arrest/apoptosis and DNA repair. All must be inactivated or overstimulated for cancer to develop. Overstimulation occurs by mutation or DNA hypomethylation. Inactivation of tumor suppressor genes happens through mutations, chromosomal instability (loss of heterozygosity), and DNA hypermethylation.

Mutations are permanent structural changes in genes. These changes may have no effect on gene function (coding of their protein; called polymorphisms), or they may be deleterious, with an impact on function. Mutations may be inherited (the cause of hereditary colorectal cancer) or acquired. They may be acquired as a result of lifestyle or environmental factors (e.g., smoking and drinking alcohol), chance, or defects in DNA repair. Because each cell has two copies of each gene, both copies of a tumor suppressor gene must be inactivated for gene expression to be lost. The time taken to inactivate both copies from environmental or lifestyle causes is one reason why carcinogenesis in the colon takes so long to occur. When one copy is lost as a result of inheritance of a mutation, the time for inactivation is reduced.

Chromosomal instability is reflected in loss of heterozygosity—that is, chromosomal events by which chromosomal instability allows chromosomal deletion or rearrangements, including nondisjunction, duplication, or translocation. The function of the genes on the rearranged chromosomes may be lost. Mutations in APC can promote chromosomal instability, the most common molecular mechanism in colorectal cancer (70% of cancers are a result of chromosomal instability) and a characteristic of hereditary cancers in FAP, MYH-associated polyposis, and polymerase proofreading polyposis ( Table 56-1 ).

Jul 15, 2019 | Posted by in GENERAL | Comments Off on Molecular Genetics of Colorectal Cancer
Premium Wordpress Themes by UFO Themes