Predicting and preventing hereditary colorectal cancer.

COLORECTAL CANCER (CRC) IS ONE OF THE MOST common malignancies in the United States and affects nearly 150 000 individuals per year. The prognosis for patients with CRC is directly related to their stage at diagnosis, with 5-year survival greater than 90% for the rare patient diagnosed with stage I cancer but less than 5% for patients with metastatic disease. Therefore, early diagnosis is essential for the prevention of the morbidity and mortality associated with CRC. This fact underlies the current recommendations for population-based screening for colon polyps and cancer, preferably using colonoscopy in individuals 50 years or older. Diet and lifestyle factors are thought to influence risk for CRC in the general population, but family history also clearly affects the individual risk for CRC, presumably due to genetic factors. A quarter of all CRC cases occur in families containing other members with CRC, suggesting a familial basis. More striking, about 3% to 4% of CRCs occur in families with a clear autosomal dominant pattern of inheritance, the most common of which is Lynch syndrome, ie, hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC was originally defined by the “Amsterdam” clinical criteria as a history of at least 3 affected family members involving 2 generations with at least 1 person diagnosed before age 50 years. Although this approach is fairly specific in identifying families with highly penetrant HNPCC, it is also overly restrictive and does not take into account the possibility of later-onset variants of the disease, the implications of extracolonic tumors, or the limitations imposed by small family size. Indeed, many families with known HNPCC do not meet the original Amsterdam Criteria. In the early 1990s, the genetic basis for Lynch syndrome was uncovered, with the discovery that germline mutations in the mismatch DNA repair genes MLH1 and MSH2 (and, subsequently, MSH6 and rarely PMS2) conferred a high susceptibility to colon and endometrial cancer and an elevated risk of other cancers, including cancers of the ovary, stomach, small bowel, hepatobiliary system, ureteral tract, brain, and other sites. This has allowed for genetic testing and counseling of individuals in families with a clinical suspicion of HNPCC to identify those for whom early and regular cancer screening may be appropriate. Indeed, use of colonoscopy in known carriers of mutations in one of these genes has been proven effective for reducing the incidence and mortality of CRC and is recommended beginning when carriers are in their early to mid 20s, at intervals of every 1 to 2 years. However, genetic testing for mismatch repair gene mutations is not perfectly sensitive or specific and is expensive, and therefore methods to better identify those individuals at significant risk for Lynch syndrome are important. Various algorithms combining family history information with molecular tumor characteristics have been developed to help in these efforts. A unique aspect of HNPCC not common to most other cancer syndromes is that specific phenotypic markers in the tumor itself can identify most cases. More than 95% of CRCs from patients with Lynch syndrome exhibit a mutational DNA pattern termed microsatellite instability (MSI), caused by the DNA repair defect intrinsic to the genetic alterations in mismatch repair genes. MSI can now be routinely detected in reference laboratories from tumor blocks, even those stored for many years. These pathologic findings have been used during the past few years to help guide genetic testing. In fact, in 1996 the Bethesda Criteria were introduced specifically to provide guidelines for selection of tumors for MSI testing, and a consensus panel of standard markers was chosen. More recently, it has been shown that immunohistochemical analysis to detect loss of mismatch repair protein expression can be performed by most pathology laboratories, although with variable success, and can help further direct genetic testing to a specific gene. These molecular pathology tests have helped greatly in identifying Lynch syndrome in individuals diagnosed with CRC, particularly when at a relatively young age. However, this approach is complicated by the fact that approximately 15% of sporadic CRCs that occur in patients without HNPCC also exhibit MSI and loss of MLH1 protein expression, due to epigenetic silencing of this gene in the