Mechanistic data establishing aneuploidy as a cause of carcinogenesis, rather than a consequence, have been difficult to generate. However, statistical approaches made possible by detailed analysis of cancer cells suggest (as might be expected) that aneuploidy tends to increase the copy number of key oncogenes and decrease the copy number of potent tumor suppressors. For example, chromosome 8, which almost never is lost and often is present in increased copies in tumor cells, is where the MYC oncogene is located. By contrast, portions of chromosome 17, where the TP53 gene is located, are often lost and are infrequently gained. Thus, tumor development and progression may be molded by changes in chromosome numbers that enhance the dosage of oncogenes while restricting the activity of tumor suppressor genes.
Fig. 6.15 AmplificationoftheNMYC geneinhumanneuroblastoma.TheNMYC gene,presentnormallyonchromosome2p,becomesamplifiedandisseeneitherasextrachromosomaldoubleminutesorasachromosomallyintegratedhomogeneous-stainingregion(HSR).Theintegrationinvolvesotherautosomes,suchas4,9,or13.(Modified from Brodeur GM, Seeger RC, Sather H, et al: Clinical implications of oncogene activation in human neuroblastomas. Cancer58:541,1986.Reprinted by permission of Wiley-Liss,Inc,a subsidiary of John Wiley & Sons, Inc.)
As discussed in Chapter 1, microRNAs (miRNAs) are non-coding, single-stranded RNAs, approximately 22 nucleotides in length, that function as negative regulators of genes. They inhibit gene expression posttranscriptionally by repressing translation or, in some cases, by messenger RNA (mRNA) cleavage. In view of their important functions in control of cell growth, differentiation, and survival, it is not surprising that accumulating evidence indicates that miRNAs also can contribute to carcinogenesis. Specifically, if the target of a miRNA is a tumor suppressor gene, then overactivity of the miRNA can reduce the tumor suppressor protein. Such miRNAs are sometimes referred to as oncomIRs. Conversely, if an miRNA inhibits the translation of an oncogene, a reduction in the quantity or function of that miRNA will lead to overproduction of the oncogene product. Such relationships have already been established by miRNA profiling of several human tumors. For example, downregulation or deletion of certain miRNAs in some leukemias and lymphomas results in increased expression of BCL2, an anti-apoptotic gene. Thus, by negatively regulating BCL2, such miRNAs behave as tumor suppressor genes. Dysregulation of other miRNAs that control the expression of the RAS and MYC oncogenes also has been detected in lung tumors and in certain B-cell leukemias, respectively.
You will recall from Chapter 1 that epigenetics refers to reversible, heritable changes in gene expression that occur without mutation. Such changes involve posttranslational modifications of histones and DNA methylation, both of which affect gene expression. In normal, differentiated cells, the major portion of the genome is not expressed. These regions of the genome are silenced by DNA methylation and histone modifications. On the other hand, cancer cells are characterized by a global DNA hypomethylation and selective promoter-localized hypermethylation. Indeed, it has become evident during the past several years that tumor suppressor genes are sometimes silenced by hypermethylation of promoter sequences, rather than by mutation. In addition, genome-wide hypomethylation has been shown to cause chromosomal instability and can induce tumors in mice. Thus, epigenetic changes may influence carcinogenesis in many ways. As an added wrinkle, deep sequencing of cancer genomes has identified mutations in genes that regulate epigenetic modifications in many cancers. Thus, certain genetic changes in cancers may be selected because they lead to alterations of the “epigenome” that favor cancer growth and survival.