Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

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human cancers. Mutations in the p53 gene can occur in virtually every type of cancer including lung, breast, and colon cancer—the three leading causes of cancer death. 2 Sometimes called the “ guardian of the genome ,” the p53 gene acts as a molecular police officer that prevents the propagation of genetically damaged cells. 2 Located on the short arm of chromosome 17, the p53 gene normally senses DNA damage and assists in DNA repair by caus- ing arrest of the cell cycle in G 1 and inducing DNA repair or initiating apoptosis in a cell that cannot be repaired. 2,3 With homologous loss of p53 gene activity, DNA dam- age goes unrepaired and mutations occur in dividing cells leading to malignant transformations. The p53 gene also appears to initiate apoptosis in radiation- and chemotherapy-damaged tumor cells. Thus, tumors that retain normal p53 function are more likely to respond to such therapy than tumors that carry a defective p53 gene. 2 The RB gene was isolated in studies involving a malignant tumor of the eye known as retinoblastoma . The tumor occurs in a hereditary and sporadic form and becomes evident in early life. Approximately 60% of cases are sporadic, and the remaining 40% are heredi- tary, inherited as an autosomal dominant trait. 2 Known as the “two hit” hypothesis of carcinogenesis, both nor- mal alleles of the RB gene must be inactivated for the development of retinoblastoma (Fig. 7-6). 2,3 In heredi- tary cases, one genetic change (“first hit”) is inherited from an affected parent and is therefore present in all somatic cells of the body, whereas the second mutation (“second hit”) occurs in one of the retinal cells (which already carries the first mutation). In sporadic (nonin- herited) cases, both mutations (“hits”) occur within a single somatic cell, whose progeny then form the cancer. The RB gene represents a model for other genes that act similarly. In persons carrying an inherited mutation, such as a mutated RB allele, all somatic cells are per- fectly normal, except for the risk of developing cancer. That person is said to be heterozygous or carrying one mutated gene at the gene locus. Cancer develops when a person becomes homozygous with two defective genes for the mutant allele, a condition referred to as loss of heterozygosity. 2 For example, loss of heterozygos- ity is known to occur in hereditary cancers, in which a mutated gene is inherited from a parent and other con- ditions (e.g., radiation exposure) are present that cause mutation of the companion gene, making an individual more susceptible to cancer. Epigenetic Mechanisms In addition to mechanisms that involve DNA and chro- mosomal structural changes, there are molecular and cellular mechanisms termed “epigenetic” mechanisms that involve changes in the patterns of gene expression without a change in the DNA. 18 Epigenetic mechanisms may “silence” genes, such as tumor-suppressor genes, so that even if the gene is present, it is not expressed and a cancer-suppressing protein is not made. One such mechanism of epigenetic silencing is by methylation of the promoter region of the gene, a change that prevents transcription and causes gene inactivity. Genes silenced

B

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Mutant Rb gene

Normal Rb gene

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Retinoblastoma

Retinoblastoma

by hypermethylation can be inherited, and epigenetic silencing of genes can be considered a “first hit” in the “two hit” hypothesis described earlier. 19 MicroRNAs (miRNA) are small, noncoding, single- stranded ribonucleic acids (RNAs), about 22 nucleotides in length, which function at the post-transcriptional level as negative regulators of gene expression. 2,3,20 miRNAs pair with messenger RNA (mRNA) containing a nucle- otide sequence that complements the sequence of the microRNA, and through the action of the RNA-induced silencing, mediate post-transcriptional gene silencing. miRNAs have been shown to undergo changes in expres- sion in cancer cells, and frequent amplifications and dele- tions of miRNA loci have been identified in a number of human cancers, including those of the lung, breast, colon, pancreas, and hematopoietic systems. 3 They can participate in neoplastic transformation by increasing the expression of oncogenes or reducing the expression of tumor suppressor genes. For example, down-regulation or deletion of certain miRNAs in some leukemias and lymphomas results in increased expression of BCL2, an FIGURE 7-6. Pathogenesis of retinoblastoma.Two mutations of the mutant retinoblastoma (Rb) gene lead to development of neoplastic proliferation of retinal cells. (A) In the familial form all offspring become carriers of the mutant Rb gene. A second mutation affects the other Rb gene locus after birth. (B) In the sporadic form, both mutations occur after birth.