Gatekeepers and Cancer susceptibility genes are divided into “gatekeepers” and “caretakers” (59). Gate-
Caretakers keeper genes control cellular proliferation and are divided into oncogenes and tumor suppressor genes. In general, oncogenes stimulate cell growth and proliferation, and tumor suppressor genes reduce the rate of cell proliferation or induce apoptosis. Gatekeepers prevent the development of tumors by inhibiting growth or promoting cell death. Examples of gatekeeper genes include the tumor suppressor gene p53 and the retinoblastoma gene.
Caretaker genes preserve the integrity of the genome and are involved in DNA repair (stability genes). The inactivation of caretakers increases the likelihood of persistent mutations in gatekeeper genes and other cancer-related genes. The DNA mismatch repair genes, MLH1, MSH2, and MSH6, are examples of caretaker genes.
Hereditary Cancer Most cancers are caused by spontaneous somatic mutations. However, a small percentage of cancers arise on a heritable genomic background. About 12% of all ovarian cancers and about 5% of endometrial cancers are considered to be hereditary (60,61). Germline mutations require additional mutations at one or more loci for tumorigenesis to occur. These
Table 6.4 Hereditary Cancer Syndromes Associated with Gynecologic Tumors mutations occur via different mechanisms, for example, via environmental factors such as ionizing radiation or mutations of stability genes. Characteristics of hereditary cancers include diagnosis at a relatively early age and a family history of cancer, usually of a specific cancer syndrome, in two or more relatives. Hereditary cancer syndromes associated with gynecologic tumors are summarized in Table 6.4.
Various cancer-causing genetic and epigenetic mechanisms are described. On the genomic level, gain of function gene mutations can lead to a conversion of proto-oncogenes into oncogenes, and loss of function gene mutations can inactivate tumor suppressor genes.
Epigenetic changes include DNA methylation, which can cause inactivation of tumor suppressor gene expression by preventing the correct function of the associated promoter sequence. Collectively, these genetic and epigenetic changes are responsible for the development of cancer characterized by the ability of cells to invade and metastasize, grow independently of growth factor support, and escape from antitumor immune responses.
Oncogenes Oncogenes comprise a family of genes that result from gain of function mutations of their normal counterparts, proto-oncogenes. The normal function of proto-oncogenes is to stimulate proliferation in a controlled context. Activation of oncogenes can lead to stimulation of cell proliferation and development of a malignant phenotype. Oncogenes were initially discovered through retroviral tumorigenesis. Viral infection of mammalian cells can result in integration of the viral sequences into the proto-oncogene sequence of the host cell. The integrated viral promoter activates transcription from the surrounding DNA sequences, including the proto-oncogene. Enhanced transcription of the proto-oncogene sequences results in the overexpression of growth factors, growth factor receptors, and signal transduction proteins, which results in stimulation of cell proliferation. One of the most important group of viral oncogenes is the family of ras genes, which include c-H(Harvey)-ras, c-K(Kirsten)-ras, and N(Neuroblastoma)-ras.