Tumor Suppressor Genes Tumor suppressor genes are involved in the development of most cancers and are usually inactivated in a two-step process in which both copies of the tumor suppressor gene are mutated or inactivated by epigenetic mechanisms like methylation (62). The most commonly mutated tumor suppressor gene in human cancers is p53 (63). The p53 protein regulates transcription of other genes involved in cell cycle arrest such as p21. Up-regulation of p53 expression is induced by DNA damage and contributes to cell cycle arrest, allowing DNA repair to occur. p53 also plays an important role in the initiation of apoptosis. The most common mechanism of inactivation of p53 differs from the classic two-hit model. In most cases, missense mutations that change a single amino acid in the DNA binding domain of p53 results in overexpression of nonfunctional p53 protein in the nucleus of the cell.
The identification of tumor suppressor genes was facilitated by positional cloning strategies.
The main approaches are cytogenetic studies to identify chromosomal alterations in tumor specimens, DNA linkage techniques to localize genes involved in inherited predisposition to cancer, and examination for loss of heterozygosity or allelic alterations among studies in sporadic tumors. Comparative genomic in situ hybridization (CGH) allows ﬂuorescence identification of chromosome gain and loss in human cancers within a similar experiment.
Stability Genes The third class of cancer genes is “stability genes,” which promotes tumorigenesis in a way different from tumor suppressor genes or amplified oncogenes. The main function of stability genes is the preservation of the correct DNA sequence during DNA replication (caretaker function) (64). Mistakes that are made during normal DNA replication or induced by exposure to mutagens can be repaired by a variety of mechanisms that involve mismatch repair genes, nuclear-type excision repair genes, and base excision repair genes. The inactivation of stability genes potentially leads to a higher mutation rate in all genes. However, only mutations in oncogenes and tumor suppressor genes inﬂuence cell proliferation and confer a selective growth advantage to the mutant cell. Similar to tumor suppressor genes, both alleles of stability genes must be activated to cause loss of function.
Genetic Aberrations Gene replication, transcription, and translation are imperfect processes, and the fidelity is less than 100%. Genetic errors may result in abnormal structure and function of genes and proteins. Genomic alterations such as gene amplification, point mutations, and deletions or rearrangements were identified in premalignant, malignant, and benign neoplasms of the female genital tract (65) (Fig. 6.9).
Amplification Amplification refers to an increase in the copy number of a gene. Amplification results in enhanced gene expression by increasing the amount of template DNA that is available for transcription. Proto-oncogene amplification is a relatively common event in malignancies of the female genital tract. The HER2/neu proto-oncogene, also known as c-erbB-2 and HER2, encodes a 185 kDa transmembrane glycoprotein with intrinsic tyrosine kinase activity. It belongs to a family of transmembrane receptor genes that includes the epidermal growth factor receptors (erbB-1), erbB-3, and erbB-4. HER2/neu interacts with a variety of different cellular proteins that increase cell proliferation. Overexpression of HER2/neu was demonstrated in about 30% of breast cancers, 20% of advanced ovarian cancers, and as many as 50% of endometrial cancers (66). High tissue expression of HER2/neu is correlated with a decreased overall survival, particularly in patients with endometrial cancer.