When counseling cancer susceptibility gene mutation carriers who are considering childbearing, it is important to address the issues listed above while maintaining sensitivity to the potential parents' personal beliefs.
Determining the Test to be Used
Genetic testing is highly specialized. A given test is usually performed in only a small number of laboratories. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colon cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition, e.g., Lynch syndrome can be due to mutations in one of several mismatch repair genes.
In some genes, the same mutation has been found in multiple, apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. Other genes have reported founder mutations as well. The presence of founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, approximately 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations. Also, for genes in which large genome rearrangements are founder mutations, ordering additional testing using different techniques may be needed.
Also, allelic heterogeneity (i.e., different mutations within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) gene mutations are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC mutations cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk.[8,9] In addition, other disorders may be part of the FAP spectrum. Mutations in a certain portion of the APC gene also predispose to retinal changes, for example, when mutations in a different region of APC predispose to desmoid tumors. Thus, selection of the appropriate genetic test for a given individual requires considerable knowledge of genetic diagnostic methods, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; and Genetics of Medullary Thyroid Cancer for more information.)