Download 22. Oncogenes

BIOL 311 Human Genetics
Fall 2006
Lecture: Cancer Genetics: Oncogenes
Reading Chap. 17 and Chapters 3 and 4 Weinberg, R. A. (2007) The Biology of
Cancer. Garland Science, New York, NY.
Outline:
1. Cancer as a genetic disease
2. Discovery of oncogenes
3. Activation of oncogenes
4. Cancer testing and profiling
1. Cancer as a genetic disease
 Cancer runs in families: Hereditary cancers of the breast, colon and retina
 Agents that damage DNA increase risk of cancer
 Many mutagens are carcinogens
Cancers involve multiple mutations in different genes
Oncogenes: Genes that promote cancer. Encode proteins involved in growth, cell
signaling, gene regulation, or that prevent cell death. Mutation leads to dominant gain of
function.
Tumor suppressors: Genes that in normal form prevent cancer. Encode transcription
factors, proteins that control cell cycle, DNA repair enzymes. Mutation leads to recessive
loss of function.
2. Discovery of oncogenes
1960's study of oncogenic retroviruses
retroviruses:
 RNA is genetic material
 Encode reverse transcriptase, enzyme that makes DNA from RNA
 Genome contains genes for envelop proteins (env), reverse transcriptase (pol),
coat proteins (gag)
 An additional gene is (oncogene) present in oncogenic retroviruses, for example
src oncogene is present in Rous sarcoma virus, an oncogenic retrovirus associated
with sarcoma (muscle tumor) in chickens
Normal cells contain proto-oncogenes: normal forms of genes for proteins adopted by
oncogenic retroviruses.
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Oncogenes are mutated or overexpressed versions of cellular proteins
Function
Example
Growth factors
sis, platelet derived growth factor
Receptors
erb-B, epidermal growth factor receptor
Cell signaling proteins
Transcription factors
Cell cycle proteins
Cell death proteins
ras, G-protein
fos, jun, myc
mdm2
bcl-2
Assay for detecting activated oncogenes, ultimately used to clone human ras
Transfection of mouse fibroblasts with DNA from cancers; identify "transformed cells",
cells with more cancer-like characteristics. Isolate and clone DNA for oncogene. Special
trick for identifying the human oncogene from transfected mouse cells--human DNA
contains Alu family repeats, mouse DNA does not.
3. Ways in which oncogenes can become activated
amplification
hundreds of extra copies made
i.e. erb-b2 (her-2/neu)
growth factor receptor associated with some breast cancers
point mutation
single base on DNA is changed
i.e. ras causes GTP binding protein to remain in "on" position and to not cycle to GDP
form
translocation
chromosome rearrangement involving non-homologous chromosomes
i.e. bcr-abl fusion oncoprotein associated with chronic myeloid leukemia
translocation involves abl gene on chromosome 9 and bcr gene on chromosome 22
Fig. 17-4 Philadelphila chromosome
Leukemia: cancer of blood forming stem cells
Burkitt's lymphoma, solid tumor of lymphocytes
T(8:14) translocation of myc into Ig heavy chain gene, associated with 75-85% of
patients; other cases associated with different translocations
4. Cancer testing and profiling
 molecular methods of diagnosis
 test DNA of cancer cells vs. normal cells
 karyotype analysis, cancer cells vs. normal cells
molecular profiles for diagnosis/treatment
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microarrays Fig. 17-18
a. identify tissue of origin (primary tumor) based on molecular markers
b. molecular profiles may distinguish tumor types
c. drug sensitivity profiles
particular genotypes may be resistant to certain drugs
d. predict clinical outcome
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