Germline cancer genetics became a reality with the cloning of the tumor suppressor gene RB1 for hereditary retinoblastoma in 1986 by Friend and Weinberg. The existence of cancer susceptibility genes had been predicted by Knudson and Strong in the so-called "two-hit" hypothesis that was developed based on observations that there were families in which cancers clustered and occurred at younger ages, more often bilaterally in paired organs or as multiple primary tumors, and far more frequently than they did otherwise in the general population. In 2015 there have been hundreds of cancer susceptibility genes identified. Most code for proteins that are involved in DNA repair or other regulatory processes rather than structural proteins. In classical cancer genetics, individuals with cancer or with a family history of the disease may seek evaluation for the possible presence of a cancer predisposition syndrome. If the gene for that syndrome is known, blood or saliva from a family member most likely to carry a predisposing mutation is submitted for analysis to one of the commercial labs. The best candidate in the family would have had a tumor that is a component of the syndrome diagnosed at an early age, for example. Molecular analysis of the germline can be focused on candidate genes (e.g. MMR genes for Lynch syndrome, PTEN for Cowden's syndrome) or performed as part of a panel of cancer susceptibility genes by NGS now available from a number of commercial laboratories. However, incidental identification of germline mutations may now occur in the process of molecular analysis of tumors performed in order to identify therapeutic targets, in the course of which a mutation in a gene that can confer hereditary predisposition may be found. Separate testing of germline material would be indicated to determine whether or not the identified mutation was acquired, and therefore somatic, or germline, which could have implications not only for the patient but also for the family. For some types of cancer, the presence of an underlying hereditary predisposition can affect treatment recommendations or surveillance for additional primary cancers in survivors as well as family members (BRCA1/2 mutations in hereditary breast or ovarian cancer, TP53 mutations in Li Fraumeni Syndrome and radiation oncogenesis, With current whole exome and whole genome analyses being offered to adults and in the prenatal setting, incidental identification of germline mutations in cancer predisposition genes as incidental findings have been part of discussions by genetics and ethicists. Mutations identified in dominant cancer susceptibility genes are on the list of those that should be disclosed in the statement by the American College of Medical Genetics, though there remains some controversy around this issue.
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