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Genetics of Cancer
Ömer Faruk Bayrak
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“Cancer is, in essence, a genetic disease. Although
cancer is complex, and environmental and other
nongenetic factors clearly play a role in many stages of
the neoplastic process, the tremendous progress made
in understanding tumorigenesis in large part is owing to
the discovery of the genes, that when mutated, lead to
cancer.”
Bert Vogelstein (1988)
NEJM 1988; 319:525-532.
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Cancer: review of molecular genetics
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Cancer cells
Genetic basis for cancers
Types of cancer
Causes of cancer
Cancer warning signs
Prevention, detection, treatment
Definition of Cancer
• Cancer is a disease characterized by the
uncontrolled proliferation of cells.
• The normal mechanisms that regulate cellular
growth and division break down.
• This breakdown results from mutations that
overcome the normal limits to the number of
cell divisions that can take place before a cell
dies.
Cancer
1. Oncogenesis may be due to:
a. Spontaneous genetic changes,
such as spontaneous gene or
chromosome mutations.
b. Exposure to mutagens or
radiation.
c. The action of genes introduced
by tumor viruses.
The 3 phases in the development of cancer
cells
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Initiation – a single cell
undergoes a mutation that
causes it to divide
repeatedly
•
Promotion – a tumor
develops and cells within
the tumor mutate
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Progression – a cell
mutates in such a way that
allows it to invade
surrounding tissue
Stages of Cancer
Progression
• Primary cells
• Immortalization
(Benign)
• Transformation
• Metastasis
Relationship of the Cell Cycle to Cancer
Regulation of Cell Division in Normal Cells
1. Cell differentiation occurs as cells proliferate to form tissues.
a. Cell differentiation correlates with loss of ability to proliferate, with the most highly
specialized cells terminally differentiated.
b. Terminally differentiated cells have a finite life span, and are replaced with new
cells produced from stem cells.
c. Stem cells are capable of self-renewal.
d. Proliferation of eukaryotic cells is described by the cell cycle:
i. M is mitotic phase. The rest of the cell cycle is interphase.
ii. During G1 the cell monitors its size and environment.
(1) If conditions are appropriate, it moves into S phase (DNA synthesis), and
completes the cycle with G2 and M.
(2) A cell that does not commit to DNA replication may enter G0 for a long
period, then reenter the cell cycle and proliferate.
2. Normal cell cycle is controlled in several ways. Most
important are signal transduction pathways.
a. Extracellular factors bind to surface receptors, transmembrane
proteins that relay signals into the cell.
b. Factors include (Figure 18.2):
i. Growth factors that stimulate cell division.
ii. Growth-inhibiting factors that inhibit cell division.
c. Healthy cells produce progeny only when the balance of
stimulatory and inhibitory signals favors cell division.
d. Neoplastic cells reproduce without constraint, sometimes
because of mutations in inhibitory or stimulatory factor genes.
Fig. 18.2a General events for regulation of cell division in normal cells
Chapter 18 slide 13
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Fig. 18.2b General events for regulation of cell division in normal cells
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Characteristics of cancer cells
 Lack differentiation and do not contribute to body functioning
 Have abnormal nuclei that are enlarged and may have an abnormal
number of chromosomes
 Unlimited ability to divide
one way is through turning on the telomerase gene that allows telomeres on
chromosomes to continually be built thus allowing a cell to divide over and over
again
 Form tumors
Benign tumors are usually encapsulated and do not invade adjacent tissue while
a cancerous tumor usually is not encapsulated and eventually invades
surrounding tissue
 Can divide without growth factors
 Become abnormal gradually through a multistage process
 Undergo angiogenesis and metastasis
Cancer Spreads Step-by-Step
Cancer is a Genetic Disease
• Cancer is a genetic disease that develops in a
predictable sequence of steps
 Carcinogenesis
• Transformation of a normal cell into a cancerous cell
• Step-by-step transformation
A Common Type of Colorectal Cancer
May Develop by These Steps
Colon cancer results from genetic
alterations in multiple genes
Inherited mutations in the APC gene dramatically increase
risk of colon cancer
Fig. 18.15 A multistep molecular event model for the development of hereditary
adenomatous polyposis (FAP), a colorectal cancer
Chapter 18 slide 20
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
The Multistep Nature of Cancer
1. Cancer induction may require accumulation of 6–7 independent mutations over
several decades, typically involving:
a. Conversion of proto-oncogenes to oncogenes.
b. Inactivation of tumor suppressor genes.
2. An example is Vogelstein’s model for a form of colorectal cancer, hereditary
FAP (Figure 18.15).
a. Mutation of both alleles of a tumor suppressor gene on chromosome 5, APC
(adenomatous polyposis coli), causes increased cell growth.
b. Hypomethylation of the DNA leads to a benign tumor (adenoma class I).
c. Mutation of the chromosome 12 ras proto-oncogene allows cells to form a larger
benign tumor (adenoma class II).
d. If both copies of DCC, a tumor suppressor gene on chromosome 18, are lost, an
even larger adenoma class III results.
e. Mutation of both p53 alleles on chromosome 17 results in conversion to a
carcinoma.
f. Other gene losses result in the cancer metastasizing.
g. Other paths are possible, but in all cases deletions of APC and mutations of ras
occur before deletions of DCC and p53.
The Two-Hit Mutation Model for Cancer
1. Cancers can be caused by viruses, but most result from mutations in cellular genes.
Usually these mutations have accumulated over time, and research has identified
the genes involved.
2. The incidence of cancer falls into two categories:
a. Sporadic cancers, the more frequent type, do not appear to have an hereditary cause.
b. Familial (hereditary) cancers run in families. Retinoblastoma provides an example
(Figure 18.3).
i. Retinoblastoma is the most common eye tumor in children birth to 4 years. Early
treatment (usually gamma radiation) is over 90% effective.
ii. Retinoblastoma has two forms:
(1) Sporadic retinoblastoma (60%) develops in children with no family history
of retinoblastoma, and occurs in one eye (unilateral tumor).
(2) Hereditary retinoblastoma (40%) patients typically develop multiple tumors
involving both eyes (bilateral tumors).
(a) Onset is usually earlier in the hereditary form.
(b) Siblings and offspring often develop the same type of tumor.
(c) Pedigrees of affected families are consistent with a single gene responsible for
retinoblastoma.
3. Knudson (1971) proposed the 2-hit mutational model, that two mutations were
required for development of retinoblastoma (Figure 18.4).
a. In sporadic retinoblastoma, the child starts with two wild-type alleles (RB+/RB+).
i. Both alleles must mutate to produce the disease genotype (RB/RB).
ii. The probability of both mutations occurring in the same cell is low, so only one
tumor forms.
b. In hereditary retinoblastoma, the child starts out heterozygous (RB/RB+).
i. Only one mutation is needed for tumor formation (RB/RB).
ii. Mutations resulting in loss of heterozygosity (LOH) are likely in rapidly dividing
cells, and multiple tumors occur.
4. In Knudson’s model:
a. Retinoblastoma alleles are recessive, because only homozygotes (RB/RB) develop
tumors.
b. However, in pedigree analysis, the disease appears to be dominant. This is because:
i. Heterozygous individuals (RB/RB+) are predisposed to the cancer, since only one
mutation is required for the neoplasm. Families with one allele already mutated will
have a significant incidence of the disease.
ii. Homozygous dominant individuals (RB+/RB+) develop the cancer only when both
alleles in the same cell are mutated. Therefore, most children in the general
population do not develop the disease.
5. This hypothesis is supported by later studies of the chromosomes of retinoblastoma
patients, which:
a. Mapped the gene to 13q14.1-q14.2 (long arm of chromosome 13).
b. Showed that the gene encodes a growth inhibitory factor (tumor suppressor).
6. Retinoblastoma is rare among cancers because a single gene is critical for its
development. In most cases, cancers result from a series of mutations in different
genes for growth and division.
Fig. 18.4 Knudson’s two-hit mutation model
Chapter 18 slide 24
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Some Tumors Are Cancer, Others Are Not
Hyperplasmia
• Cells in a tissue overgrow
• Resulting defined mass: tumor (neoplasm)
– Benign, e.g., moles
• Slow growth
• Expands in the same tissue; does not spread
• Cells look nearly normal
– Malignant
• Rapid growth
• Invades surrounding tissue and metastasizes
• Cell differentiation usually poor
Some Tumors Are Cancer, Others Are Not
Dysplasia
• Abnormal change in the size, shape, and
organization of cells in a tissue
• Often an early step toward cancer
– Microscopic characteristics of cancer cells
– Behave differently from normal cells
Cancer Cells Are Abnormal in Their
Growth and Appearance
Telomeres
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Chromosome tips
TTAGGG repeats
Shorten with each cell division
Nerve cells have short telomeres
– Do not divide very often
• Gametes have long telomeres
– Must divide many, many times
– Telomerase adds TTAGGG repeats
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Cancer Cells
• Produce telomerase
• Immortal
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Henrietta Lacks
• Died of cervical cancer
in 1951
• Biopsy of her cancer is
still alive!
• Cultures of her cancer
cells in labs world
wide
• Called HeLa cells
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HeLa Cells
• Used to develop vaccine
for polio
• Divide every 24 hours
• Often contaminate
research labs
• New species evolved from
humans
– One celled microorganism
• Reproduces on its own
• Has all the characteristics of
every other living species
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Cancer Cells
• Mutated cells
• Do not respond to cell
cycle control signals
– Do not repair DNA
damage in interphase
• Grow continuously
• Transplantable
– Can inject into an
animal and it will
continue to grow
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Cancer Cells (cont.)
• Different appearance
– Some are more round
• Heritable
– Offspring of CA cells are also cancerous
• Dedifferentiated
– Less specialized than the cells they arose from.
• Loss of contact inhibition
– Do not stop dividing when they crowd other cells
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Cancer Cells (cont.)
• Invasive
– Secrete chemical to cut paths through healthy
tissue
• Angiogenesis
– Stimulate blood vessels to grow and feed CA
• Metastasize
– Travel by bloodstream or lymphatic system to start
new tumors
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Normal Moles Are Common Examples
of Benign Growths
Main Features of Benign and
Malignant Tumors
A Cancer Cell’s Structure Is Abnormal
• Cancer is a result of a series of mutations in
the cell’s genes
– Larger cell nucleus and less cytoplasm
– Loss of structural specialization
– Cytoskeleton shrinks
– Plasma membrane proteins could be lost or
altered
– New plasma membrane proteins may appear
– Changes passed on to cell’s descendants
Genes and Cancer
1. Three classes of genes are mutated frequently in cancer:
a. Proto-oncogenes, whose products normally stimulate cell
proliferation.
b. Tumor suppressor genes, whose products normally inhibit
proliferation.
c. Mutator genes, whose products ensure accurate replication and
maintenance of the genome.
Proto-oncogenes
• Cellular homologues of viral oncogenes (a.k.a.
normal cellular oncogenes, c-onc)
• e.g, v-src and c-src; very similar genes (few
a.a. different)
• c-onc genes a lot of conservation in structure
among species
• c-onc’s have introns; v-onc’s do not
Oncogenes
1.Tumor viruses induce infected cells to
proliferate and produce a tumor. There are two
types, based on the viral genome:
a. RNA tumor viruses transform cells by introducing
viral oncogenes. (An oncogene is any gene that
stimulates unregulated proliferation.)
b.DNA tumor viruses do not carry oncogenes, and
use other mechanisms to transform the cell.
Oncogenes are usually dominant
(gain of function)
• cellular proto-oncogenes that have been mutated
(and “activated”)
• cellular proto-oncogenes that have been captured by
retroviruses and have been mutated in the process
(and “activated”)
• virus-specific genes that behave like cellular protooncogenes that have been mutated to oncogenes (i.e.,
“activated”)
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Five types of proteins encoded by proto-oncogenes participate in
control of cell growth:
Class I: Growth Factors
Class II: Receptors for Growth Factors and Hormones
Class III: Intracellular Signal Transducers
Class IV: Nuclear Transcription Factors
Class V: Cell-Cycle Control Proteins
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Amino acid substitutions in Ras family proteins
(inactivates GTPase)
amino acid position
Ras gene
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Tumor
c-ras (H, K, N)
Gly
Ala
Gln
normal cells
H-ras
Gly
Val
Cys
Arg
Val
Gly
Gly
Ala
Ala
Ala
Ala
Ala
Ala
Ala
Leu
Gln
Gln
Gln
Gln
Lys
Arg
lung carcinoma
bladder carcinoma
lung carcinoma
lung carcinoma
colon carcinoma
neuroblastoma
lung carcinoma
K-ras
N-ras
Murine sarcoma virus
H-ras
K-ras
Arg
Ser
Thr
Thr
Gln
Gln
Harvey strain
Kirsten strain
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Activation mechanisms of proto-oncogenes
proto-oncogene --> oncogene
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CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS
Neoplasm
Translocation
Proto-oncogene
Burkitt lymphoma
t(8;14) 80% of cases
t(8;22) 15% of cases
t(2;8)
5% of cases
c-myc1
Chronic myelogenous
leukemia
t(9;22) 90-95% of cases
bcr-abl2
Acute lymphocytic
Leukemia
t(9;22) 10-15% of cases
bcr-abl2
1c-myc
is translocated to the IgG locus, which results in its activated expression
2bcr-abl
fusion protein is produced, which results in a constitutively active abl kinase
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GENE AMPLIFICATION
Oncogene
Amplification
Source of tumor
c-myc
~20-fold
leukemia and lung carcinoma
N-myc
5-1,000-fold
neuroblastoma
retinoblastoma
L-myc
10-20-fold
small-cell lung cancer
c-abl
~5-fold
c-myb
5-10-fold
acute myeloid leukemia
colon carcinoma
c-erbB
~30-fold
epidermoid carcinoma
K-ras
4-20-fold
30-60-fold
colon carcinoma
adrenocortical carcinoma
chronic myoloid leukemia
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The result:
• Overproduction of growth factors
• Flooding of the cell with replication signals
• Uncontrolled stimulation in the intermediary
pathways
• Cell growth by elevated levels of transcription
factors
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Tumor suppressor genes
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Normal function - inhibit cell proliferation
Absence/inactivation of inhibitor --> cancer
Both gene copies must be defective
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KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES
Familial RB (%30)
rb
RB
RB
LOH
Tumor cells
rb
RB
Normal cells
rb
Inactivation of a tumor suppressor
gene requires two mutations, inherited
mutation and somatic mutation.
Normal cells
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KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES
Normal
Cells
RB
RB
RB
RB
RB
Mutation
RB
LOH
Tumor cells
Inactivation of a tumor
suppressor gene
requires two somatic
mutations.
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TUMOR SUPPRESSOR GENES
Disorders in which gene is affected
Gene (locus)
Function
Familial
Sporadic
DCC (18q)
cell surface
interactions
unknown
colorectal
cancer
WT1 (11p)
transcription
Wilm’s tumor
lung cancer
Rb1 (13q)
transcription
retinoblastoma
small-cell lung
carcinoma
p53 (17p)
transcription
Li-Fraumeni
syndrome
breast, colon,
& lung cancer
BRCA1(17q)
transcriptional
breast cancer
breast/ovarian
tumors
BRCA2 (13q)
regulator/DNA repair
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CELL CYCLE
Daugther cell
Gateway
Mitosis
Growth
Factors
S
DNA
CELL CYCLE
replication
Cell cycle
inhibitors
Control Point
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Rb gene
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Rb protein controls cell cycle moving past G1 checkpoint
Rb protein binds regulatory transcription factor E2F
E2F required for synthesis of replication enzymes
E2F - Rb bound = no transcription/replication
Growth factor --> Ras pathway
--> G1Cdk-cyclin synthesized
Active G1 Cdk-cyclin kinase phosphorylates Rb
Phosphorylated Rb cannot bind E2F --> S phase
–
–
Disruption/deletion of Rb gene
Inactivation of Rb protein
--> uncontrolled cell proliferation --> cancer
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p53
• Phosphyorylated p53 activates transcription of p21 gene
• p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity)
• Cell cycle arrested to allow
DNA to be repaired
• If damage cannot be repaired
--> cell death (apoptosis)
•
Disruption/deletion of p53 gene
•
Inactivation of p53 protein
--> uncorrected DNA damage
--> uncontrolled cell proliferation --> cancer
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p53
• Most mutations in DBD
• cannot bind to target genes, so targets not
transcribed
• recessive loss-of-function mutations
• also important in cellular stress response
• normal p53 important in DNA damage repair
DNA REPAIR GENES
These are genes that ensure each strand of genetic information is accurately
copied during cell division of the cell cycle.
Mutations in DNA repair genes lead to an increase in the frequency of
mutations in other genes, such as proto-oncogenes and tumor suppressor genes.
i.e. Breast cancer susceptibility genes (BRCA1 and BRCA2)
Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1,
PMS1, PMS2) have DNA repair functions. Their mutation will cause
tumorigenesis.
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Molecular
mechanisms of
DNA double
strand break
repair
BRCA1/2
Van Gent et al, 2001
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Chromosomal rearrangements and
cancer
• CML- chronic myelogenous leukemia
• Philadelphia chromosome - reciprocal
translocation between chromosomes 9 and 22
• c-alb oncogene involved (on chromosome 9);
ber gene on chromosome 22
pBRCA1 and pBRCA2
• Mutant forms of these TS genes implicated in
breast and ovarian cancer
• brca1- map to ch 17; brca 2 - map to ch 13
• 220-350 kd proteins
• in nucleus - putative transcription factors
• mutations in these about 7% of all breast
cancers and 10% of ovarian cancers
• carriers high probability of disease
Comparing these genes in normal and
cancer cells
Types of cancer
• Oncology – study of cancer
• Carcinomas: cancers of the epithelial tissue
• Adenocarcinomas: cancers of glandular epithelial
cells
• Sarcomas: cancers of muscle and connective
tissues
• Leukemias: cancers of the blood
• Lymphoma: cancers of lymphatic tissues
Genetic causes of cancer
• Examples of genes associated with cancer:
– BRCA1 and BRCA2 – tumor-suppressor genes that are
associated with breast cancer
– RB – a tumor-suppressor gene that is associated with an
eye tumor
– RET – proto-oncogene that is associated with thyroid
cancer
• Mutations of these genes predispose individuals to
certain cancers but it takes at least one more
acquired mutation during their lifetime to develop
cancer
CANCER QUICK COURSE—WHAT CAN YOU DO TO PREVENT/TREAT?
Environmental causes of cancer
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Radiation:
– Environmental factors such as UV light (in sunlight or tanning lights)
and x-rays can cause mutation in DNA
•
Organic chemicals:
– Tobacco smoke: increases cancer of lungs, mouth, larynx and others
– Pollutants: substances such as metals, dust, chemicals and pesticides
increase the risk of cancer
•
Viruses:
– Hepatitis B & C: virus that can cause liver cancer
– Epstein-Barr virus: can cause Burkitt’s lymphoma
– Human papillomavirus: can cause cervical cancer
Seven warning signs of cancer
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Change in bowel or bladder habits
A sore that does not heal
Unusual bleeding or discharge
Thickening or lump in breast or elsewhere
Indigestion or difficulty in swallowing
Obvious change in wart or mole
Nagging cough or hoarseness
Other ways to detect cancer
• Tumor marker tests – blood tests for tumor
antigens/antibodies
– CEA (carcinoembryonic antigen) antigen can be detected in someone
with colon cancer
– PSA (prostate-specific antigen) test for prostate cancer
• Genetic tests – tests for mutations in proto-oncogenes and
tumor-suppressor genes
– RET gene (thyroid cancer)
– P16 gene (associated with melanoma)
– BRCA1 (breast cancer)
• A diagnosis of cancer can be confirmed by performing a
biopsy
Standard cancer treatments
• Surgery – removal of small cancers
• Radiation therapy – localized therapy that causes
chromosomal breakage and disrupts the cell cycle
• Chemotherapy – drugs that treat the whole body that kills
cells by damaging their DNA or interfering with DNA synthesis
• Bone marrow transplants – transplant bone marrow from one
individual to another
CANCER QUICK COURSE—WHAT CAN YOU DO TO PREVENT/TREAT?
Newer cancer therapies
• Immunotherapy – inject immune cells that are genetically
engineered to bear the tumor’s antigens
• Passive immunotherapy – antibodies that are linked to
radioactive isotopes or chemotherapeutic drugs are injected
into the body
• p53 gene therapy – a retrovirus in clinical trial that is injected
into the body where it will infect and kill only tumor cells
(cells that lack p53 = tumor cells)
• Angiogenesis inhibition - Angiostatin and endostatin are drugs
in clinical trials that appear to inhibit angiogenesis