Chapter 079. Cancer Genetics (Part 10)

Figure 79-8A cDNA array experiment. RNA is prepared from cells, reverse transcribed to cDNA, and labeled with fluorescent dyes (typically green for normal cells and red for cancer cells). The fluorescent probes are mixed and hybridized to the cDNA array. Each spot on the array is a cDNA fragment that represents a different gene. The image is then captured with a fluorescence camera; red spots indicate higher expression in tumor compared with reference while green spots represent the opposite. Yellow signals indicate equal expression levels in normal and tumor specimens. After clustering analysis of multiple arrays, the results are...
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Chapter 079. Cancer Genetics (Part 10) Chapter 079. Cancer Genetics (Part 10)Figure 79-8 A cDNA array experiment. RNA is prepared from cells, reversetranscribed to cDNA, and labeled with fluorescent dyes (typically green fornormal cells and red for cancer cells). The fluorescent probes are mixed andhybridized to the cDNA array. Each spot on the array is a cDNA fragment thatrepresents a different gene. The image is then captured with a fluorescencecamera; red spots indicate higher expression in tumor compared with referencewhile green spots represent the opposite. Yellow signals indicate equal expressionlevels in normal and tumor specimens. After clustering analysis of multiple arrays,the results are typically represented graphically using Treeview software, whichshows, for each sample, a color-coded representation of gene expression for everygene on the array. In addition, with the completion of the Human Genome Project andadvances in sequencing technologies, large-scale mutational profiling of thecancer genome has become possible. Hundreds of genes from a given pathway(MAPK pathway, for example) or from a gene family can be systematicallysequenced in a large number of cancers in order to identify genes that are crucialto human oncogenesis. This approach has been used to identify several noveltargets in various cancers. For example, B-RAF mutations were identified in alarge fraction of melanomas and PIK3CA mutations were identified in largefractions of colon, breast, and hepatocellular cancers. Most recently, this approachhas been applied to an unbiased set of genes including about two-thirds of all thoseknown to encode proteins. Hundreds of genes not previously implicated in cancerswere shown to be altered in breast and colorectal cancers. The Future A revolution in cancer genetics has occurred in the past 25 years.Identification of cancer genes has led to a better understanding of thetumorigenesis process and has had important repercussions on all fields ofbiology. In spite of these spectacular advances, however, there has been littleoverall improvement in cancer death rates. It is hoped that, as the molecularmechanisms of cancer initiation and development continue to be elucidated, noveltherapies based on pathophysiology rather than empiricism will emerge. Time willtell whether these strategies will rely on novel combinations or dosing schedulesof conventional drugs or will be based on new approaches such as those involvinggene therapy or immunotherapy. In addition, a better understanding of themolecular pathways and genetic alterations in cancer cells may lead to thedevelopment of sensitive strategies for early detection of cancer. Further Readings Garber JE, Offit K: Hereditary cancer predisposition syndromes. J ClinOncol 23:276, 2005 [PMID: 15637391] Golub TR et al: Molecular classification of cancer: Class discovery andclass prediction by gene expression monitoring. Science 286:531, 1999 [PMID:10521349] Jallepalli PV, Lengauer C: Chromosome segregation and cancer: Cuttingthrough the mystery. Nat Rev Cancer 1:109, 2001 [PMID: 11905802] Loeb LA: Mutator phenotype may be required for multistagecarcinogenesis. Cancer Res 51:3075, 1991 [PMID: 2039987] Munger K: Disruption of oncogene/tumor suppressor networks duringhuman carcinogenesis. Cancer Invest 20:71, 2002 [PMID: 11853005] Parsons DW et al: Colorectal cancer: Mutations in a signaling pathway.Nature 436:792, 2005 [PMID: 16094359] Strausberg RL et al: In silico analysis of cancer through the CancerGenome Anatomy Project. Trends Cell Biol 11:S66, 2001 Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet9:138, 1993 [PMID: 8516849] Bibliography Fearon ER, Cho KR: The molecular biology of cancer, in Principles andPractices of Medical Genetics, AE Emery, DL Rimoin (eds). New York, ChurchillLivingstone, 1996 Hesketh R: The Oncogene and Tumour Suppressor Gene Facts Book, 2ded. San Diego, Academic Press, 1997 Vogelstein B, Kinzler KW: The Genetic Basis of Human Cancer, 2d ed.New York, McGraw-Hill, 2002