Chapter 20 - Genetics of cancer:

 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)
Oncogenesis arises from:

1. Spontaneous gene or chromosome mutations.

2. Exposure to mutagens or radiation.

3. Activity of genes introduced by tumor viruses.

4. 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.
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.

• Two types of growth factors:

1. Growth factors stimulate cell division.

2. 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.
Fig. 20.3, Regulation of cell division by signal transduction.
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.

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 (derived from

cellular proto-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 (no transformation
per se).
Retroviruses and oncogenes:

Retrovirus =

• 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.
Fig. 20.4, Structure of a retrovirus
Retroviruses and oncogenes:

• All RNA tumor viruses are retroviruses.

• RNA viral oncogenes are altered forms of normal host “growth factor”
or “growth-inhibiting factor” 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.

Retroviruses and oncogenes:

Three types of genes occur in most retroviruses:

1. gag (group antigen): codes the protein core

2. pol (polymerase): codes reverse transcriptase and an enzyme

for proviral integration.

3. env (envelope): codes envelope glycoproteins.

Nononcogenic retroviruses possess no oncogenes and direct their own

life cycle (e.g., HIV infects and destroys T helper cells).
Retroviruses and oncogenes:

Oncogenic retroviruses (v-onc) transform the cell and cause cancer

(also called transducing viruses)

• Different retroviruses carry different oncogenes responsible for

different types of cancer (e.g. v-src in RSV).

• Most oncogenic retroviruses (but not RSV) are defective and do not
possess a full set of virus life-cycle genes.

(transform cells but do not produce progeny viruses)

• Defective retroviruses produce progeny with the help of a normal

virus that co-infects cell and supplies missing gene products.

• When coinfected - a helper virus supplies missing gene products ->

assists with viral expression and replication.
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:

• Growth & growth-inhibiting factors, regulatory genes involved

in the control of cell multiplication.

• Protein kinases, add phosphate groups to target proteins,

important in signal transduction pathways.

• Mutations relax cell control of growth, allowing unregulated

proliferation.
DNA tumor viruses:

• Do not carry oncogenes.

• Transform cells to the cancerous state through actions of genes

(and gene products) in the viral genome.

• Examples include viruses in the following groups:

•
• papovaviruses (warts and human cervical cancer)
• hepatitis B
• Herpes
• Adenoviruses
• pox viruses

• DNA tumor virus gene products induce production of cellular DNA

replication enzymes for viral replication.

• Viral gene products stimulate cells to proliferate unrestrained.

Tumor suppressor genes:

• First discovered in 1960s by Henry Harris.

• Harris fused tumor cells with normal cells and discovered some of
the hybrid cells were normal.

• Harris hypothesized that the normal cells produced gene products

that suppressed uncontrolled cell proliferation.

• Some cancers show deletions of specific sites (tumor repressor

genes) that normally inhibit cell growth and division.

• e.g., breast cancer, colon cancer, lung cancer

• Two mutations (one on each allele) are required to inactivate

tumor suppressor genes.
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 several genes, including WAF1, and interacts with at

least 17 cellular and viral proteins.

• Transgenic mice with deletions of both p53 alleles are viable, but
100% develop cancer by ten months of age.
Fig. 20.10, Effects of DNA damage and normal (non-mutant) p53
lead to apoptosis, resulting in
cell growth arrest.
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.

Multi-step nature of cancer:

• Cancer is a stepwise process, typically requiring accumulation of

mutations in a number of genes.

• ~6-7 independent mutations typically occur over several decades:

• Conversion of proto-oncogenes to oncogenes

• Inactivation of tumor suppressor genes

Carcinogens-chemicals:

Carcinogen = natural or artificial agents that increases the frequency of

mutations and cancerous cells.

• Chemicals are responsible for more cancers than viruses.

• Sir Percival Pott first correlated scrotal cancer with exposure to

coal soot in chimney sweeps in 18th century Britain.

• Many present day cancers arise from occupational exposure risks

to chemicals: asbestos, PVCs.

• Tobacco smoke and diet implicated in ~50-60% of U.S. cancers.

• Two types of chemical carcinogens cause point mutations:

• Direct acting carcinogens mutate DNA directly

(e.g., alkylating agents)

• Procarcinogens are metabolically converted to carcinogens

(e.g., cigarette smoke, aflatoxins [fungi], nitrosamines)
Carcinogens-radiation:

Sources of radiation include the sun, cell phones, radon gas, electric
power lines, and household appliances.

• ~2% of cancers deaths are caused by radiation.

• Ionizing radiation (x-rays, radon gas, radioactive material) can

cause leukemia and thyroid cancer.

• Ultraviolet light:

• UV-B (290-320 nm) is the main cause of sunburn and is

directly mutagenic.

• UV-A (320-400 nm) increases the effects of UV-B on skin.