Chapter 079. Cancer Genetics (Part 9) pot

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

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 exhibit CIN Normal cells possess several cell cycle checkpoints, often defined as quality-control requirements that have to be met before subsequent events are allowed to take place The spindle checkpoint, which ensures proper chromosome attachment to the mitotic spindle before allowing the

sister 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 been identified, although a few candidates mutated in a small number of tumors have been discovered The identification of the cause of CIN in tumors will likely be a formidable task, considering that several hundred genes are thought to control the mitotic checkpoint and other cellular processes assuring proper chromosome segregation Regardless of the mechanisms underlying CIN, the measurement of the number of chromosomal alterations present in tumors is now possible with both cytogenetic and molecular techniques, and several studies have shown that this information can be useful for prognostic purposes

Viruses in Human Cancer

Certain human malignancies are associated with viruses Examples include Burkitt's lymphoma (Epstein-Barr virus), hepatocellular carcinoma (hepatitis virus), cervical cancer [human papillomavirus (HPV)], and T cell leukemia (retroviruses) The mechanisms of action of these viruses are varied but always involve activation of growth-promoting pathways or inhibition of tumor-suppressor products in the infected cells For example, HPV proteins E6 and E7 bind and inactivate cellular tumor suppressors p53 and pRB, respectively Viruses are not sufficient for cancer development but constitute one alteration in the multistep process of cancer

Epigenetic Regulation of Gene Expression in Cancer

An epigenetic modification refers to a change in the genome, heritable by

cell progeny, that does not involve a change in the DNA sequence The inactivation of the second X chromosome in female cells is an example of an epigenetic mechanism that prevents gene expression from the inactivated chromosome During embryologic development, regions of chromosomes from one parent are silenced and gene expression proceeds from the chromosome of the other parent For most genes, expression occurs from both alleles or randomly from one allele or the other The preferential expression of a particular gene

exclusively from the allele contributed by one parent is called parental imprinting

and is thought to be regulated by covalent modifications of chromatin protein and DNA (often methylation) of the silenced allele

The role of epigenetic control mechanisms in the development of human cancer is unclear However, a general decrease in the level of DNA methylation has been noted as a common change in cancer In addition, numerous genes, including some tumor-suppressor genes, appear to become hypermethylated and

silenced during tumorigenesis VHL and p16INK4 are well-studied examples of

tumor-suppressor genes that are silenced through methylation in human cancers Overall, epigenetic mechanisms may be responsible for reprogramming the expression of a large number of genes in cancer and, together with the mutation of specific 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 gene expression The advent of powerful new techniques such as microarrays and serial analysis of gene expression (SAGE) has allowed the study of gene expression in neoplastic cells on a scale never before accomplished Indeed, it is now possible to identify expression levels of thousands of genes expressed in normal and cancer tissues Figure 79-8 shows a typical cDNA array experiment examining gene expression in cancer This global knowledge of gene expression allows the identification of differentially expressed genes and, in principle, the understanding

of the complex molecular circuitry regulating normal and neoplastic behaviors Such studies have led to molecular profiling of tumors, which has suggested general methods for distinguishing tumors of various biologic behaviors (molecular classification), elucidating pathways relevant to the development of tumors, and identifying molecular targets for the detection and therapy of cancer The first practical applications of this technology have suggested that global gene expression profiling can provide prognostic information not evident from other clinical or laboratory tests The National Cancer Institute, in conjunction with the National Center for Biotechnology Information, has undertaken the Cancer Genome Anatomy Project (CGAP) (http://cgap.nci.nih.gov/) to collect data on

gene expression in normal and malignant tissues and make it available on the Internet