Chapter 079. Cancer Genetics (Part 10) pptx

In addition, with the completion of the Human Genome Project and advances in sequencing technologies, large-scale mutational profiling of the cancer genome has become possible.. Hundreds

Chapter 079 Cancer Genetics

(Part 10)

Figure 79-8

A 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 typically represented graphically using Treeview software, which shows, for each sample, a color-coded representation of gene expression for every gene on the array

In addition, with the completion of the Human Genome Project and advances in sequencing technologies, large-scale mutational profiling of the cancer genome has become possible Hundreds of genes from a given pathway (MAPK pathway, for example) or from a gene family can be systematically sequenced in a large number of cancers in order to identify genes that are crucial

to human oncogenesis This approach has been used to identify several novel

targets in various cancers For example, B-RAF mutations were identified in a large fraction of melanomas and PIK3CA mutations were identified in large

fractions of colon, breast, and hepatocellular cancers Most recently, this approach

has been applied to an unbiased set of genes including about two-thirds of all those known to encode proteins Hundreds of genes not previously implicated in cancers were 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 the tumorigenesis process and has had important repercussions on all fields of biology In spite of these spectacular advances, however, there has been little overall improvement in cancer death rates It is hoped that, as the molecular mechanisms of cancer initiation and development continue to be elucidated, novel therapies based on pathophysiology rather than empiricism will emerge Time will tell whether these strategies will rely on novel combinations or dosing schedules

of conventional drugs or will be based on new approaches such as those involving gene therapy or immunotherapy In addition, a better understanding of the molecular pathways and genetic alterations in cancer cells may lead to the development of sensitive strategies for early detection of cancer

Further Readings

Garber JE, Offit K: Hereditary cancer predisposition syndromes J Clin

Oncol 23:276, 2005 [PMID: 15637391]

Golub TR et al: Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring Science 286:531, 1999 [PMID: 10521349]

Jallepalli PV, Lengauer C: Chromosome segregation and cancer: Cutting through the mystery Nat Rev Cancer 1:109, 2001 [PMID: 11905802]

Loeb LA: Mutator phenotype may be required for multistage carcinogenesis Cancer Res 51:3075, 1991 [PMID: 2039987]

Munger K: Disruption of oncogene/tumor suppressor networks during human 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 Cancer Genome Anatomy Project Trends Cell Biol 11:S66, 2001

Vogelstein B, Kinzler KW: The multistep nature of cancer Trends Genet 9:138, 1993 [PMID: 8516849]

Bibliography

Fearon ER, Cho KR: The molecular biology of cancer, in Principles and

Practices of Medical Genetics, AE Emery, DL Rimoin (eds) New York, Churchill

Livingstone, 1996

Hesketh R: The Oncogene and Tumour Suppressor Gene Facts Book, 2d

ed San Diego, Academic Press, 1997

Vogelstein B, Kinzler KW: The Genetic Basis of Human Cancer, 2d ed

New York, McGraw-Hill, 2002