Cancer arises from mutations in genes that control cell division, apoptosis, and DNA repair. There are three main classes of cancer genes: proto-oncogenes that become activated oncogenes, tumor suppressor genes that are inactivated, and mutator genes that increase mutation rates. The two-hit model explains that tumors often develop when both copies of a tumor suppressor gene acquire mutations. For example, the tumor suppressor gene RB is mutated in the inherited cancer retinoblastoma following the two-hit model. Cancer development can also be caused by viruses introducing oncogenes or through exposure to carcinogens and radiation inducing mutations.

1. Genetics ofcancer
Cell cycle and cancer
Two-hit mutation model
Oncogenes and RNA/DNA tumor viruses
Tumor suppressor genes
Mutator genes
Carcinogens: chemicals and radiation
Some basic terminology:
Oncogenesis = process of initiation of tumors (cancer) in an organism (onkos = mass; genesis = birth)
Tumor = tissue composed of cells that deviate from normal program of cell division and differentiation.
Benign tumor = tumor cells remain together in a single mass and do not invade or disrupt surrounding tissues
Malignant tumor = tumor cells invade and disrupt surrounding tissues (diagnosed as cancer,and such cells can
transform other cells to the cancerous state).
Metastasis = spread of malignant tumor cells throughout the body (typically through the blood and lymphatic system)
Howdo we define cancer?
Cancer is a group of disorders that causes cells to escape normal controls on cell division
 cancer cells divide more frequently
 cancer cells are not inhibited by contact with other cells and can form tumors
 cancer cells can invade other tissues, a process called metastasis
Oncogenesis arises from:
 Spontaneous gene or chromosome mutations.
 Exposure to mutagens or radiation.
 Activity of genes introduced by tumor viruses.
 Some cancers are inherited (individuals may be predisposed).
Cell cycle and cancer:
Cell differentiation occurs as cells proliferate to form tissues. Cell differentiation correlates with loss of ability to
proliferate; highly specialized cells are terminally differentiated. Terminally differentiated cells have a finite life span,
and are replaced with new cells produced from stem cells. Stem cells are capable of self-renewal; cells divide without
undergoing terminal differentiation.
Cell death (apoptosis) is equally important. Apoptosis is the normal outcome for most cells, and the sequence of
events must be programmed correctly. Otherwise cells don’t die when they should, and uncontrolled cell division can
result in cancer.
Chemical Signals that Control the Cell Cycle
1. Cyclin and Kinase -proteins that initiate mitosis
-requires buildup of cyclin to pair with kinase
2. Hormones -chemical signals from specialized glands that stimulate mitosis
3. Growth Factors -chemical factors produced locally that stimulate mitosis
Normal cell cycle is controlled by signal transduction:
Growth factors bind to surface receptors on the cell; transmembrane proteins relay information to the cell by signal
transduction.

2. Two types ofgrowth factors:
 Growth factors stimulate cell division.
 Growth-inhibiting factors inhibit cell division.
Healthy cells divide only when growth factor and growth-inhibiting factor balance favors cell division. Cancer cells
divide without constraint. Cancer is primarily caused by mutations in growth and growth-inhibiting factor genes,and
pathways that inhibit the normal sequence of events associated with apoptosis.
Two-hit mutation model for cancer:
Most cancers result from mutations in cellular genes. Other cancers are caused by viruses.
Two types ofcancer:
 Sporadic more frequent, no hereditary cause
 Familial less frequent, hereditary
In cancer cells, the RAS gene product is locked
into its GTP-binding shape and does not require a
signal at the receptor in order to stimulate cell
division
In response to growth factor binding at receptor,
the Ras gene product combines with GTP to
promote cell division

3. Retinoblastoma (OMIM-180200) shows sporadic and hereditary forms and fits the pattern of a two-hit model. Most
common eye tumor of children. Occurs from birth to 4 years of age. Early treatment with gamma radiation is 90%
effective.
Two-hit mutation model for retinoblastoma (OMIM-180200):
Sporadic retinoblastoma
 60% of retinoblastoma cases.
 Develops in children with no family history.
 Occurs in one eye.
Hereditary retinoblastoma
 40% of retinoblastoma cases.
 Onset typically is earlier than sporadic cases.
 Multiple tumors involving both eyes.
 Consistent pedigrees; siblings and offspring develop the same type of tumors.
Alfred Knudson’s (1971) model for retinoblastoma (OMIM-180200):
Two mutations are required for the development of
retinoblastoma.
Sporadic retinoblastoma
 Child starts with two wild type alleles (RB+/RB+).
 Both alleles must mutate to produce the disease
(RB/RB).
 Probability of both mutations occurring in the same
cell is low; only one tumor forms (e.g., one eye).
Hereditary retinoblastoma
 Child starts with heterozygous alleles (RB/RB+).
 Only one mutation is required to produce disease
(RB/RB).
 Mutations resulting in loss of heterozygosity (LOH)
are more probable in rapidly dividing cells, and
multiple tumors occur (e.g., both eyes).
Retinoblastoma was mapped to the long arm of
chromosome 13 (13q14.1-q14.2). Mutations occur in a gene
that encodes a growth inhibitory factors (a tumor suppressor
gene). Retinoblastoma is rare among cancers; most cancers
result from a series of mutations in many different genes. So
retinoblastoma is easier to treat.
Cancer and genes:
Three classes of genes frequently are mutated in cancer:
 Proto-oncogenes ( oncogenes)
 Tumor suppressor genes
 Mutator genes
Proto-oncogenes  oncogenes:
Proto-oncogenes = Proto-oncgenes are genes that possess normal gene products and stimulate normal cell
development.

4. Oncogenes = Oncogenes arise from mutant proto-oncogenes. Oncogenes are more active than normal or active at
inappropriate times and stimulate unregulated cell proliferation.
Some tumor viruses that infect cells possess oncogenes:
 RNA tumor viruses = possess viral oncogenes capable of transforming cells to a cancerous state.
 DNA tumor viruses = do not carry oncogenes, but induce cancer by activity of viral gene products on the cell
Proto-oncogene and oncogene protein products:
~100 different oncogenes have been identified.
To understand the cancer,must understand the function of protein products coded by the proto-oncogenes.
All known proto-oncogenes are involved in positive control of cell growth and division.
Two classes:
o Growth factors, regulatory genes involved in the control of cell multiplication.
o Protein kinases, add phosphate groups to target proteins, important in signal transduction pathways.
Mutations relax cell control of growth, allowing unregulated proliferation.
Retroviruses and oncogenes:
Single-stranded RNA virus that replicates via double-stranded
DNA intermediate.
RNA is converted to cDNA by reverse transcriptase.
DNA integrates into host chromosome and is transcribed.
Retroviruses typically possess:
 2 copies of a 7-10 kb ssRNA genome
 protein viral core
 glycolipid envelope (glycoproteins recognize host
cells)
Transducing retroviruses possesses oncogenes,which
can cause cancer when integrated into the host
chromosome.
All RNA tumor viruses are retroviruses.
RNA viral oncogenes are altered forms of normal host
genes that occur in the virus genome.
Examples of retroviruses include:
 Rous sarcoma virus (RSV), Feline leukemia
virus, Mouse mammary tumor virus
 Human immunodeficiency virus (HIV)
Not all retroviruses are transducing or cause cancer.
Life cycle ofa retrovirus:
First characterized in 1910 by F. Peyton Rous from a
chicken tumor, later named the Rous sarcoma virus.
1. ssRNA genome is released from the virus
particle and is reverse transcribed to dsDNA
(proviral DNA).
2. Reverse transcriptase occurs in the virus
particle and lacks 3’ to 5’ exonuclease activity
(no proofreading  lots of mutations).

5. 3. Proviral DNA and host chromosome DNA cross-over and are joined by recombination.
4. Host RNA polymerase transcribes proviral DNA and produces viral mRNAs required for the virus life cycle.
Cell Cycle Checkpoints
Genetic Mutations That Can Cause Cancer
Tumor Suppressor Genes
Genes that inhibit cell division are inactivated.
Mutation in a gene that halts the cell cycle in G1
causes retinoblastoma.
Mutation in p53, a gene that promotes apoptosis if a
cell has damaged DNA,leads to a variety of
cancers.
Mutation in BRCA1,involved in tumor suppression
and DNA repair, leads to inherited breast cancer.
p53 tumor suppressor genes:
Mutations in p53 are implicated in ~50% of human
cancers,including cancers of the: breast,brain,
liver, lung, colorectal, bladder, and blood
Development of tumors requires mutations on two
p53 alleles.
Codes a 393 amino acid protein involved in
transcription, cell cycle control, DNA repair, and
apoptosis (programmed cell death).
p53 binds to severalgenes and interacts with at least
17 cellular and viral proteins.
Genes that promote DNA repair (DNA Repair
Genes) are inactivated.
BRCA1 is a tumor suppressor involved in DNA repair. Faulty copies of BRCA1 cause inherited breast cancer.
The disease Xeroderma Pigmentosum results from a defect in excision repair.

6. Breast cancer tumor suppressor genes:
Breast cancer affects 1 in 10 women and
represents 31% of cancers in women
(~185,000 women diagnosed each year).
~5% of breast cancers are hereditary; age of
onset for hereditary breast cancer is earlier
than other forms (mutations at 2 alleles).
Many genes involved; BRCA1 and BRCA2
are thought to be tumor suppressor genes.
BRCA1 is important for homologous
recombination, cellular repair of DNA
damage, and transcription of mRNA.
Mutations in BRCA1 also are involved in
ovarian cancer.
BRCA2 plays a role in timing of mitosis in
the cell cycle.
Mutator genes:
Mutator gene increases spontaneous mutation rate of other genes.
Mutator gene products are involved in DNA replication and repair; mutations make the cell error prone.
HNPCC-OMIM 120435, Human non-polyposis colon cancer
Mutation at any one of 4 genes (hMSH2, hMLH1, hPMS1, hPMS2) leads to predisposition.
Tumor formation requires mutation at the second allele.
All four genes have homologs in yeast.
DNA blood tests are available for all four genes.