Studies of both chromosomes and nucleic acids support Boveri’s 1914 hypothesis that cancer is caused by a change in genetic material at the cellular level. Three classes of genes can be involved in neoplastic transformation.
Oncogenes arise from preexisting normal genes (protooncogenes) that have been altered by both viral and nonviral factors. As a result, the cells synthesize either normal proteins in inappropriate amounts or proteins that are aberrant in structure and function. Many of these proteins are cellular growth factors or receptors for growth factors. The net result of oncogene activation is unregulated cell division. Mutations that activate oncogenes almost always arise in somatic cells and are not usually inherited. Although some oncogenes are more likely to be activated in certain tumors, in general the same mutations may be found in neoplasia arising in different cells and tissues.
Tumor suppressor genes can be viewed as the antithesis of oncogenes. Their normal function is to suppress transformation; mutation in both alleles is necessary to obliterate this important function. The first pathogenic variant allele at any tumor suppressor gene might arise spontaneously or might be inherited; a pathogenic variant in the other allele (the “second hit”) almost always arises spontaneously but by any of a number of molecular mechanisms. These genes show considerably more tumor specificity than do oncogenes; however, although some specific mutations are necessary for certain tumors to arise, no loss of single tumor suppressor function is sufficient. Clearly, a person who inherits one copy of a pathogenic tumor suppressor gene is at increased risk that in some susceptible cell, at some time during life, the function of that gene will be lost. This susceptibility is inherited as an autosomal dominant trait. For example, a pathogenic variant in one allele of the p53 locus results in the Li-Fraumeni syndrome, in which susceptibility before age 45 years to sarcomas and other tumors occurs in males and females in successive generations. Inherited pathogenic variants in this locus also increase the risk that a second tumor will develop following radiation or chemotherapy for the first tumor, suggesting that the initial treatment may induce a “second hit” in a p53 locus in another tissue. However, inheriting a p53 pathogenic variant is not a guarantee that cancer will develop at an early age. Much more needs to be learned about the pathogenesis of neoplasia before the genetic counseling of families with a molecular predisposition to cancer is clarified. BRCA1, a gene that predisposes women to breast and ovarian cancer, is another example of a tumor suppressor gene. Women who inherit one pathogenic allele of BRCA1 have, on average, a 60–80% lifetime risk of developing breast cancer, and the average age of tumor detection is in the fifth decade. Their risk of developing ovarian cancer is 34–45%. For both females and males with certain pathogenic variants in BRCA1, the risks of colon and pancreatic cancer are increased several-fold over that of the general population.