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Genetics of Cancer
Lecture 7
Alterations in the Cell Cycle
and Gene Mutations that
Cause Cancer
How do 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
Cancer cells
grow into tumors.
Non-cancerous
cells form sheets.
Cancer cells can
invade other tissues.
Invasion and Metastasis
• Cancers spread through
invasion and metastasis.
• Invasion is the direct
migration and penetration of
cancer cells into tissues.
• Metastasis refers to the
ability of cancer cells to enter
the vasculature and migrate
to distant sites.
Control of the Cell Cycle
Mechanisms for controlling progress
through the cell cycle:
Checkpoints
Length of Telomeres
Chemical Signals from within and
outside the cell
Cell Cycle Checkpoints
Apoptosis
Checkpoint
G2
DNA Damage
Checkpoints
assembly of
components
for division
S
chromosomes
replicate
Mitosis
P M
A
T
cytokinesis
G1
cytoplasm
doubles
Spindle
Assembly
Checkpoint
Length of Telomeres
telomeres
Telomeres are
structures at the ends
of chromosomes that
shorten with each cell
division. After 50
divisions, the
shortened length of
telomeres causes
mitosis to stop.
Failure to Stop at
Cell Cycle Checkpoints
Mutation in a gene that
usually slows the cell
cycle
Failure to pause for
DNA repair
Rate of cell division is
accelerated.
Loss of control over
telomere length
Cancer cells have
telomerase, an enzyme
that elongates telomeres.
Cells continue to divide
after 50 mitoses.
Faulty DNA leads to
unregulated cell growth.
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
-produced locally that stimulate mitosis
Apoptosis: Cell Death
Signal arrives at
“death” receptor
on cell
White blood
cells destroy cell
fragments
Caspase
enzymes carry
out cell
destruction
Genetic Pathways to Cancer
• Microsatellite Instability (MSI-H)
– Deficiency in DNA mismatch repair (MMR)
• HNPCC (MSH2, MLH1, MSH6, PMS2)
• 15% sporadic (hypermethylation of MLH1 promoter)
• Chromosomal Instability (CIN)
– APC, TP53, KRAS, Loss of Heterozygosity,
aneuploid DNA content
• CpG Island Methylator Phenotype (CIMP)
– Methylation of CpG islands in promoter regions of
tumour suppressor genes
• Sporadic CRCs demonstrating MSI are a subset
Genetic Mutations That
Can Cause Cancer
Oncogenes
• Formed when proto-oncogenes that
promote cell division are improperly
activated.
May lead to
– increased expression of the gene in a
new location
– production of fusion proteins with new
functions
Oncogene
Tumor Suppressor
Gene
A series of mutations is responsible for the
development of FAP colon cancer.
The c-ras Gene
• The c-H-ras oncogene was identified by the
transfection test (homologue to the Harvey
strain of the rat sarcoma virus)
• The mutant c-H-ras protein has a mutation
that impairs its ability to hydrolyze GTP. This
keeps the mutant protein in an active
signaling mode and causes it to stimulate
cell division.
• Mutant versions of c-ras have been found
in many types of tumors.
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
Ras Proto-Oncogene
In response to growth factor
binding at receptor, the Ras
gene product combines with
GTP to promote cell division
The Philadelphia Chromosome found in
patients with Chronic Myeloid Leukemia causes
a fusion protein to be made from a combination
of genes on chromosomes 9 and 22.
Chromosomal Rearrangements:
Burkitt’s Lymphoma
• Burkitt’s lymphoma is associated with reciprocal
translocations involving chromosome 8 and a
chromosome carrying an immunoglobulin gene (2,
14, or 22).
• The translocations juxtapose c-myc to the genes for
the immunoglobulin genes, causing overexpression
of c-myc in B cells.
• The c-myc gene encodes a transcription factor that
activates genes for cell division.
A Reciprocal Translocation
Involved in Burkitt’s Lymphoma
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.
“Gatekeepers” are the genes that directly
control cell birth and cell death.
RB, p53, PTEN, APC, BRCA1 and BRCA2
“Caretakers” do not directly control cell birth or cell
death but rather control the rate of mutations
of other genes, including gatekeeper genes.
XP-A, ATM, hMSH1, hMLH2, hPMS1,hPMS2, WRN-H
Tumor growth kinetics is different for
gatekeepers and caretakers
When a gatekeeper gene
is altered through mutation, the
rate of cell birth exceeds that of cell death,
and a tumor is initiated.
When a caretaker gene is altered, the
cell accumulates mutations at a high rate
and the process of tumorigenesis is accelerated.
Rb = product of
Retinoblastoma gene,
inhibits action of E2F until
chemically modified
In Normal Cells, the Rb Gene Product
Controls the G1 S Transition
E2F = transcription factor
required to activate genes
for DNA synthesis
CDK-cyclin (intracellular
signal) modifies Rb so
the E2F can mediate
the G1S transition
People prone to retinoblastoma have one mutated copy of the Rb
gene (Rb-) and one normal copy (Rb+). Conversion of the Rb+ copy
to Rb- by mutation leads to uncontrolled growth of retinal cells.
Knudsons 2-hit mutation model for RB
Structure of RB1 protein
DNA tumor virus oncoproteins: SV40 large T, HPV E7
and Ad E1A also bind the A/B pocket and block RB
function in cell cycle regulation
p53 = transcription factor that
causes p21 to be produced
In Normal Cells, the p53 Gene Product
Acts at the G1 S Checkpoint Preventing
Entry Into S Phase If DNA Is Damaged
p21 inhibits intracellular signals
that would activate EF2
Cells with
damaged DNA
do not pass the
G1S
checkpoint
In cancer cells the mutated p53 gene
product no longer stimulates p21
production. Cells will pass the G1 S
checkpoint even when chromosomal
damage exists.
In Normal Cells, the p53 Gene Product Stimulates
Apoptosis If DNA Damage Cannot Be Repaired
p53 gives an internal
signal for apoptosis
In cancer cells, a mutated p53
gene product no longer initiates
self-destruction. Cells with
damaged DNA can divide and
more DNA damage can be
accumulated.
p53 is the most frequently mutated
of all known cancer-causing genes,
contributing to many types of cancer.
Genetic Mutations That Can Cause Cancer
DNA Repair Genes
• Genes that promote DNA repair 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.
Knudson’s Two-Hit Hypothesis
• When tumor suppressor genes are mutated,
a predisposition to develop cancer often
follows a dominant pattern of inheritance.
• The mutation is usually a loss-of-function
mutation in the tumor suppressor gene.
• Cancer develops only if a second mutation in
somatic cells knocks out the function of the
wild-type allele.
p53 is a Transcription Factor
• Most mutations in that inactivate p53 are in the DNAbinding domain (DBD) and impair its ability to bind
enhancer sequences in its target genes. Mutations in
this domain are “lost-of-function.”
• OD: homo-oligomerazation domain. Mutations in this
domain are “dominant negative.”
• TAD: transcriptional activation domain
APC controls proliferation and
differentiation of cells
• pAPC mutations are associated with adenomatous
polyposis coli, which often leads to colorectal cancer.
• pAPC regulates the renewal of cells in the epithelium
of the large intestine. Loss of pAPC function results in
the formation of polyps.
• pAPC binds to catenin, which binds to transcription
factors. Cells with mutations in pAPC lose their ability
to control catenin levels.
• Familial adenomatous polyposis (FAP):rare
autosomal dominant dissease.
APC controls proliferation and
differentiation of cells
phMSH2 regulate genomewide instability
• The phMSH2 protein is a homologue of the
bacterial and yeast MutS protein, which is
involved in DNA repair.
• Mutations in the hMSH2 gene are associated
with hereditary nonpolyposis colorectal cancer
(HNPCC), a dominant autosomal condition.
• Cells in HNPCC tumors exhibit genetic
instability.
BRCA1 and pBRCA2 regulate DN
repair.
• Mutations in the tumor suppressor genes
BRCA1 (Ch17) and BRCA2 (Ch13) have
been implicated in hereditary breast and
ovarian cancer.
• Both genes encode proteins that are localized
in the nucleus and have putative
transcriptional activation domains.
• pBRCA1 and pBRCA2 may be involved in
DNA repair in human cells.