Chapter 079. Cancer Genetics (Part 9)

Chromosomal Instability in Solid Tumors Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes; these chromosomes also exhibit structural alterations such as translocations, deletions, and amplifications. Again, colon cancer has proven to be a particularly useful model for the study of chromosomal instability (CIN). As described above, some familial cases are characterized by the presence of MIN. Interestingly, MIN and CIN appear to be mutually exclusive in colon cancer, suggesting that they represent alternative mechanisms for the generation of a mutator phenotype in this cancer (Fig. 79-2). Other cancer types rarely exhibit MIN but almost always...
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Chapter 079. Cancer Genetics (Part 9) Chapter 079. Cancer Genetics (Part 9) Chromosomal Instability in Solid Tumors Solid tumors are generally highly aneuploid, containing an abnormalnumber of chromosomes; these chromosomes also exhibit structural alterationssuch as translocations, deletions, and amplifications. Again, colon cancer hasproven to be a particularly useful model for the study of chromosomal instability(CIN). As described above, some familial cases are characterized by the presenceof MIN. Interestingly, MIN and CIN appear to be mutually exclusive in coloncancer, suggesting that they represent alternative mechanisms for the generation ofa mutator phenotype in this cancer (Fig. 79-2). Other cancer types rarely exhibitMIN but almost always exhibit CIN. Normal cells possess several cell cyclecheckpoints, often defined as quality-control requirements that have to be metbefore subsequent events are allowed to take place. The spindle checkpoint, whichensures proper chromosome attachment to the mitotic spindle before allowing thesister chromatids to separate, has been shown to be deficient in certain cancers.The genes that, when mutated, may cause CIN have in general not yet beenidentified, although a few candidates mutated in a small number of tumors havebeen discovered. The identification of the cause of CIN in tumors will likely be aformidable task, considering that several hundred genes are thought to control themitotic checkpoint and other cellular processes assuring proper chromosomesegregation. Regardless of the mechanisms underlying CIN, the measurement ofthe number of chromosomal alterations present in tumors is now possible withboth cytogenetic and molecular techniques, and several studies have shown thatthis information can be useful for prognostic purposes. Viruses in Human Cancer Certain human malignancies are associated with viruses. Examples includeBurkitts lymphoma (Epstein-Barr virus), hepatocellular carcinoma (hepatitisvirus), cervical cancer [human papillomavirus (HPV)], and T cell leukemia(retroviruses). The mechanisms of action of these viruses are varied but alwaysinvolve activation of growth-promoting pathways or inhibition of tumor-suppressor products in the infected cells. For example, HPV proteins E6 and E7bind and inactivate cellular tumor suppressors p53 and pRB, respectively. Virusesare not sufficient for cancer development but constitute one alteration in themultistep process of cancer. Epigenetic Regulation of Gene Expression in Cancer An epigenetic modification refers to a change in the genome, heritable bycell progeny, that does not involve a change in the DNA sequence. Theinactivation of the second X chromosome in female cells is an example of anepigenetic mechanism that prevents gene expression from the inactivatedchromosome. During embryologic development, regions of chromosomes fromone parent are silenced and gene expression proceeds from the chromosome of theother parent. For most genes, expression occurs from both alleles or randomlyfrom one allele or the other. The preferential expression of a particular geneexclusively from the allele contributed by one parent is called parental imprintingand is thought to be regulated by covalent modifications of chromatin protein andDNA (often methylation) of the silenced allele. The role of epigenetic control mechanisms in the development of humancancer is unclear. However, a general decrease in the level of DNA methylationhas been noted as a common change in cancer. In addition, numerous genes,including some tumor-suppressor genes, appear to become hypermethylated andsilenced during tumorigenesis. VHL and p16INK4 are well-studied examples oftumor-suppressor genes that are silenced through methylation in human cancers.Overall, epigenetic mechanisms may be responsible for reprogramming theexpression of a large number of genes in cancer and, together with the mutation ofspecific genes, are likely to be crucial in the development of human malignancies. Gene Expression and Mutational Profiling in Cancer The tumorigenesis process, driven by alterations in tumor suppressors,oncogenes, and epigenetic regulation, is accompanied by changes in geneexpression. The advent of powerful new techniques such as microarrays and serialanalysis of gene expression (SAGE) has allowed the study of gene expression inneoplastic cells on a scale never before accomplished. Indeed, it is now possible toidentify expression levels of thousands of genes expressed in normal and cancertissues. Figure 79-8 shows a typical cDNA array experiment examining geneexpression in cancer. This global knowledge of gene expression allows theidentification of differentially expressed genes and, in principle, ...