Genetics of Colorectal Cancer

Irfan M. Hisamuddin, MD; Vincent W. Yang, MD, PhD

In This Article

Classification of Cancer-Causing Genes

Genes whose mutations can cause cancer (cancer-causing genes) can be broadly divided into 2 classes: tumor suppressor genes (TSGs) and oncogenes. TSGs encode proteins that either inhibit cell proliferation or promote cell death (apoptosis). Loss of 1 of more of these "brakes" from the cell cycle contributes to the development of many cancers. A unique type of TSG belongs to a group of enzymes or proteins that are responsible for repairing DNA damage. Although these genes do not directly inhibit cell proliferation, their loss results in the accumulation of mutations in other genes that are essential in the control of cell proliferation. Because generally only 1 copy of a TSG is sufficient for function, both alleles of a TSG must be inactivated in order to promote tumor development. TSGs therefore act recessively.

The first TSG was identified in patients with hereditary retinoblastoma. Children with this syndrome inherit a single defective copy of the retinoblastoma susceptibility (Rb) gene. Inactivation of the second copy of Rb, usually occurring shortly after birth, results in the development of retinoblastoma (multiple tumors in the retinas of both eyes), often in both eyes. In contrast, individuals with sporadic retinoblastoma inherit 2 normal copies of Rb, each of which has to be inactivated before a tumor can form. Because the latter event is an unlikely occurrence, sporadic retinoblastoma develops much later in life and usually involves only 1 eye.

If TSGs are the "brakes" in cells, oncogenes represent the "gas pedal." Cells have many proto-oncogenes that are essential for the development of the organism. Mutations in these proto-oncogenes can sometimes lead to their activation, converting them into oncogenes. Once activated, oncogenes can greatly accelerate cell proliferation and often contribute to tumor formation. Sometimes, mutations that cause activation of cell surface receptors for various growth factors can also result in tumor formation. For example, many breast cancers contain excessive amounts of the Her2 receptor, which binds epidermal growth factor (EGF). Here, even very low levels of EGF, which normally is insufficient to stimulate cell proliferation, can significantly accelerate the growth of Her2-overexpressing breast cancer cells. On the basis of this finding, a monoclonal antibody specific for Her2 is now used clinically to treat certain breast cancers.


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