Oncology & Cancer Case Reports

Cancer susceptibility gene mutations are usually inherited (passed from parent to child) and may be seen within families. Knowing if a person has a cancer susceptibility gene mutation may help prevent, diagnose, and treat cancer. Not all people who have a cancer susceptibility gene mutation will develop cancer. Low-Penetrance Cancer-Susceptibility Alleles Although Mendelian inheritance of mutations in cancer-susceptibility genes is associated with a subset of human cancer, there are also mutations and variants in the genome that do not confer this type of strong predisposition yet still increase cancer risk, either generally or specifically for one tumor type. These variants may identify additional risk factors associated with known cancer-related genes or may identify genes which have less obvious or direct roles in tumorigenesis and yet may also contribute to the cancer phenotype. These low-penetrance alleles confer a significantly increased risk of sporadic tumors. For example, the I1307K allele of the adenomatous polyposis coli (APC) gene confers a twofold risk for sporadic colon carcinoma as well as its hereditary role in familial adenomatous polyposis. These low-penetrance alleles are inherited in the same way as the higher-penetrance mutations; however, only a proportion of those who inherit these mutations will develop tumors. Thus, the typical autosomal dominant cancer predisposition inheritance pattern that we see with highly penetrant alleles is not obvious, and the few tumor cases observed in a family can be mistakenly interpreted as sporadic cases. Mutations of these genes may also contribute to tumors in a dosage-dependent fashion, such that the degree of cancer susceptibility is dependent on the number of functional copies of the gene. For example, carriers of mutations of the ataxia-telangiectasia mutated (ATM) gene have a 3.5- to 5-fold relative risk of developing breast cancer as compared to the total population.