Inheritance of Colorectal Cancer

Abstract

Inheritance is involved in up to one third of colon cancer cases. Highly penetrant inherited syndromes account for approximately 3%, while more common, but less penetrant inherited factors play a role in the remainder. Approaches to recognizing each of these categories and syndromes, using genetic testing for diagnosis where indicated, and accomplishing proper cancer screening and surveillance will be outlined in this review.

Figure 1. Causes of Colon Cancer

The majority of colon cancers are thought to arise from environmental factors and are called sporadic. Approximately one-third arise from moderately penetrant inherited susceptibility, possibly interacting with environmental factors. The genes involved in this type of inheritance have not yet been defined, although a number of candidate genes have been suggested. Up to 3% of colon cancer cases arise in the setting of inherited syndromes, where the risk of colon cancer is very high. These include hereditary nonpolypsis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and several extremely rare hamartomatous polyposis syndromes (see table 2 and table 3). (Modified from Burt, 2000 [1].

Figure 2. Genetic Testing Approach for Lynch Syndrome

There are several approaches to determine who should have genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. If Amsterdam II criteria are met (see Table 4), one may proceed directly to germline genetic testing. If there is a strong family history of colon cancer, but these criteria are not met, the Bethesda Guidelines should be applied. If any of these are met, the tumor should be tested for microsatellite (MSI) instability and/or tumor immunochemistry (IHC) should be done. IHC examines the expression of the mismatch repair genes. If MSI is positive or IHC testing indicates lack of expression of one of the mismatch repair proteins, then one should proceed to germline genetic testing. This testing usually involves a peripheral blood draw and lymphocyte DNA for the testing. (Modified from [27]

Figure 3. Testing All Colon Cancers as an Approach to Lynch Syndrome

Another approach to genetic testing for HNPCC or Lynch syndrome begins with testing all colon cancers by immunohistochemical methods looking for expression of one of the mismatch repair genes. Ten percent to 15% of tumors will show lack of expression although only 1% to 3% of tumors will actually be from patients with Lynch syndrome. Testing the tumor for a specific BRAF mutation can eliminate about half of the sporadic tumors, substantially decreasing the number of persons that should then undergo germline genetic testing.