Genetics of Colorectal Cancer

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

In This Article

Genetic Testing

The approach to genetic testing in individuals and family members at risk for CRC requires a well thought-out rationale, with a systematic identification of the proband, the at-risk family, appropriate pretest genetic counseling, laboratory investigations, and, finally, posttest counseling and clinical follow-up. If a mutation is detected in a proband, family members should be offered testing. If a family member tests negative, then he should be reassured as to the lack of need for further screening but be reminded of the fact that he still has the background population risk.

Genetic testing for FAP is performed using a commercially available in vitro synthesized protein assay to detect truncated APC protein.[13] The sensitivity of this test is approximately 65%, with false-negative results seen in about 20% of patients. Therefore, the disease is ruled out for an individual only if there is no mutation found in an affected family member.[38] Genetic testing for HNPCC is more complex because any 1 of a host of genes may be mutated, although defects in MLH1 and MSH2 are responsible for the disease in about 85% of cases. Furthermore, only 50% of patients who meet the Amsterdam criteria will have positive results on MLH1 and MSH2 testing, raising concerns about false negatives. Additional guidelines have been devised in an attempt to increase the yield for identification of HNPCC ( Table 1 ).[39] Many of the newly published guidelines include examination of the tumors for MSI and level of MMR expression by immunohistochemistry.[40]

The issue of genetic testing has significant ethical connotations. The anxiety associated with testing, the implications of false-negative results, the financial aspects of testing, vis a vis insurance coverage, and the privacy issues associated with genetic testing should all be carefully and judiciously addressed. The process of testing should involve thorough genetic counseling of the patient and family members, both before and after the test. Testing should be offered after close consultation with the patient and family and in those cases where a reasonable correlation and benefit is evident.


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