Chapter 079. Cancer Genetics (Part 10) pptx

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 fluorescen
t 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 fluorescenc
e
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 resul
ts 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: He
reditary 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]
Jallepal
li 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: I
n 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