Screening For Genetic Susceptibility

Because of the low prevalence of mutations in the general population and the cost of testing, genetic screening is not appropriate for all individuals. The first step in risk assessment is accurate family history. This essential, cost-effective tool allows primary care physicians to initiate evaluation (141). Information on three generations for both maternal and paternal relatives should be gathered, including race, age, cancer type, age at diagnosis, and age at death. Information should be updated at each visit, as family history is not static. Based on history, patients at elevated risk may be referred for additional evaluation by an oncologist or cancer geneticist. In 1996, the American Society of Clinical Oncology (ASCO) recommended testing for genetic susceptibility only when: "(1) the person has a strong family history of cancer or very early-age onset of disease; (2) the test can be adequately interpreted; and (3) the results will influence the medical management of the patient or family member" (142). Before

DNA testing, all patients should undergo genetic counseling to carefully detail potential risks and benefits.

For patients at risk for HBOC, the ASCO panel suggested that testing is most likely to be of value for patients with at least a 10% probability of carrying a mutation in BRCA1 or BRCA2. A summary of these patients is detailed in Table 5. Aside from identifying specific subsets of patients based on personal and family history, some investigators have developed risk assessment models to detect potential patients who may benefit from testing. Frank et al. (143) developed a statistical model to predict the probability of BRCA1 or BRCA2 mutation for women diagnosed with breast cancer before the age of 50 by utilizing personal and family history information. Couch et al. (144) incorporated the average age of breast cancer diagnosis in the family, and whether the family history included breast cancer only or breast and ovarian cancer to predict the probability of a BRCA1 mutation. In both models, the likelihood of mutation rises with any history of ovarian cancer.

For individuals at risk for HNPCC mutations, the Amsterdam and Bethesda criteria are used to identify those likely to benefit from genetic screening (145). The Bethesda criteria stipulate that individuals with either two relatives (in small families) or two first-degree relatives with colon cancer, combined with a third relative with early-onset colon cancer or endometrial cancer should undergo genetic testing. The Amsterdam criteria recommend testing for individuals meeting any of the following conditions:

1. A family history of two or more successive generations affected by colorectal cancer,

2. One or more relatives diagnosed with colorectal cancer before the age of 50,

3. Colon cancer diagnosed in at least three relatives (one must be related to the other two), or

4. An increased incidence of other cancers (such as ovary, uterus, stomach, urinary tract, small bowel, and bile duct).

After genetic testing, careful counseling is necessary to interpret the meaning of both positive and negative test results. A positive result indicates that an individual carries a potential disease-causing mutation. In families where a specific mutation has been identified, the benefit for testing family members is clear. The family members testing negative for the mutation may be reassured that their risk, although not zero, is not elevated more than that in the general population. A negative test result must be carefully interpreted. False-negative results may occur when an individual's mutation arises in a gene that was not tested, or the mutation is not detected by polymerase chain reaction techniques (in the case of a mutation in a noncoding region or a large deletion). In cases, where multiple family members are affected, a single member's negative test should not preclude testing other relatives because a given individual might simply have suffered a case of sporadic cancer. As negative results are not necessarily informative in families without a specific defined mutation, physicians should still consider appropriate clinical management options for patients at high-risk by history, but with negative test results.

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