Genetics of Colorectal Cancer

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

In This Article

The Genetic Paradigm of Colorectal Cancer Formation

In 1990, Fearon and Vogelstein[2] presented evidence for a multistep genetic model for the formation of CRC. This model is based on the understanding that CRC is the result of mutations in key genes, including the inactivation of TSGs and the activation of oncogenes. Moreover, accumulation of mutations occurs in a sequential manner, with mutations of some genes preceding that of others. This genetic paradigm is shown in Figure 2. As seen, there are 2 different pathways that lead to the formation of CRC. One route is through inactivation of the TSG, adenomatous polyposis coli (APC), which accounts for approximately 85% of all CRC and is mutated in the germline of patients with FAP. The other pathway for development of CRC is through the mutational inactivation of a family of proteins involved in DNA mismatch repair (MMR), including MSH2, MLH1, and PMS2. MMR mutation is found in approximately 15% of all sporadic CRC and is responsible for the HNPCC syndrome.

The genetic paradigm of colorectal cancer. The formation of CRC requires the sequential mutation of several genes. This includes the inactivation of TSGs (in green) and activation of oncogenes (in red). There are 2 independent pathways that can cause CRC, depending upon which TSG is first inactivated. Inactivation of the APC gene is found in about 85% of sporadic CRC, and inactivation of the mismatch repair genes, including MSH2, MLH1, and PMS2, is found in the remaining 15%.Key: COX-2 = cyclo-oxygenase-2.

Mutations in the MMR genes cause genetic defects in other genes that are involved in growth control and behave like TSGs. The APC pathway of CRC formation often includes activation of oncogenes such as COX-2 and K-RAS and inactivation of additional TSGs such as DCC/DPC4 and p53 (Figure 2).


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