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Genetics and Cancer
Cancer
Cancer is one of the most common and severe diseases seen in clinical
medicine.
Statistics show that cancer in some form strikes more than one third of the
population,
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Accounts for more than 20% of all deaths
In developed countries, is responsible for more than 10% of the
total cost of medical care.
Cancer is invariably fatal if it is not treated.
Early diagnosis and early treatment are vital, and identification of
persons at increased risk of cancer before its development is an
important objective of cancer research.
Sporadic Cancer
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Approximately 9095% of all cancers
are sporadic and
result from mutations
in somatic cells
Age of diagnosis
typically later in life
Usually not inherited
Hereditary Cancer
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5-10% are inherited
and caused by
mutations in germline
cells
Several affected family
members
Earlier than average
age of onset
A particular pattern of
cancers noted
Individuals with more
than one primary
tumour site
The Genetic Basis of
Cancer
Regardless of whether a cancer occurs sporadically in an
individual, as a result of somatic mutation, or repeatedly in
many individuals in a family as a hereditary trait (germline
mutation), cancer is a genetic disease.
Genes in which mutations cause cancer fall into two distinct
categories: oncogenes and tumor-suppressor genes (TSGs).
Oncogenes
•An oncogene is a mutant allele of a proto-oncogene, a class of normal
cellular protein-coding genes that promote growth and survival of cells.
•Oncogenes facilitate malignant transformation by stimulating
proliferation or inhibiting apoptosis.
•Oncogenes encode proteins such as:
•proteins in signaling pathways for cell proliferation
•transcription factors that control the expression of growth-promoting
genes
•inhibitors of programmed cell death machinery
Tumor-Suppressor
Genes (TSGs)
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Gatekeeper TSGs control cell growth. Gatekeeper genes block tumor
development by regulating the transition of cells through checkpoints
("gates") in the cell cycle or by promoting programmed cell death and,
thereby, controlling cell division and survival. Loss-of-function
mutations of gatekeeper genes lead to uncontrolled cell
accumulation.
Gatekeeper TSGs encode:
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regulators of various cell-cycle checkpoints
mediators of programmed cell death
Tumor-Suppressor
Genes (TSGs)
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Caretaker TSGs protect the integrity of the genome. Loss of
function of caretaker genes permits mutations to accumulate in
oncogenes and gatekeeper genes, which, in concert, go on to
initiate and promote cancer.
Caretaker TSGs encode:
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proteins responsible for detecting and repairing mutations
proteins involved in normal chromosome disjunction during mitosis
components of programmed cell death machinery
Tumor Initiation
Different types of genetic alterations are responsible for initiating cancer.
These include mutations such as:
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gain-of-function mutations, including gene amplification, point
mutations, and promoter mutations, that turn one allele of a protooncogene into an oncogene
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chromosome translocations that cause misexpression of genes
or create chimeric genes encoding proteins with novel functional
properties
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loss of function of both alleles, or a dominant negative mutation
of one allele, of TSGs.
Tumor Progression
Once initiated, a cancer progresses by accumulating
additional genetic damage, through
•mutations or
•epigenetic silencing of caretaker genes that encode
the machinery that repairs damaged DNA and
• maintains cytogenetic normality
A further consequence of genetic damage is altered
expression of genes that promote vascularization and
the spread of the tumor through local invasion and
distant metastasis.
Oncogenes
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Activating or gain-offunction mutations, including
gene amplification, point
mutations, and promoter
mutations, that turn one allele
of a proto-oncogene into an
oncogene
Mechanisms of Activation of
Proto-oncogenes
Mechanism
Type of Gene Activated
Result
Regulatory mutation
Growth factor genes
Increased expression
Structural mutation
Growth factor receptors, signaltransducing proteins
Allows autonomy of expression
Translocation, retroviral insertion,
gene amplification
Transcription factors
Overexpression
Activation of Oncogenes by Chromosome
Translocation
Oncogenes are not always the result of
a DNA mutation.
In some instances, a proto-oncogene is
activated by a chromosome mutation,
usually through translocation.
More than 40 oncogenic chromosome
translocations have been described,
primarily in sporadic leukemias and
lymphomas but also in a few rare
connective tissue sarcomas.
The best known example is the
translocation between chromosomes 9
and 22 that is seen in chronic
myelogenous leukemia (CML)
Characteristic chromosome translocations in
selected human malignancies
Neoplasm
Burkitt lymphoma
Chromosome
Translocation
Percentage of Cases
Proto-oncogene Affected
t(8;14)(q24;q32)
80%
(8;22)(q24;q11)
15%
t(2;8)(q11;q24)
5%
Chronic myelogenous
leukemia
t(9;22)(q34;q11)
90%-95%
BCR-ABL
Acute lymphocytic
leukemia
t(9;22)(q34;q11)
10%-15%
BCR-ABL
Acute lymphoblastic
leukemia
t(1;19)(q23;p13)
3%-6%
TCF3-PBX1
Acute promyelocytic
leukemia
t(15;17)(q22;q11)
∼95%
RARA-PML
Chronic lymphocytic
leukemia
t(11;14)(q13;q32)
10%-30%
BCL1
Follicular lymphoma
t(14;18)(q32;q21)
∼100%
BCL2
MYC
Tumor Suppressor Genes
The Two-Hit origin of cancer
• Loss of both alleles of a TSGs also play
an important role in the pathogenesis of
many common sporadic cancers,
although in this instance, both alleles
are inactivated by two somatic events
occurring in the same cell.
Knudsen’s “two hit”
hypothesis
Tumor Suppressor Genes
The Two-Hit origin of cancer
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The "two-hit" model is now widely accepted as
the explanation for many familial cancers
besides retinoblastoma, including familial
adenomatous polyposis coli, familial breast
cancer, neurofibromatosis type 1 (NF1),
and a rare form of familial cancer known as
Li-Fraumeni syndrome.
Selected Tumor-Suppressor Genes
Gene
Gene Product and Possible Function
DISORDERS IN WHICH THE GENE IS AFFECTED
Familial
Gatekeepers
RB1
p110
Cell cycle regulation
TP53
Retinoblastoma
Sporadic
small cell lung carcinomas,
breast cancer
p53
Li-Fraumeni syndrome
Cell cycle regulation
Decreases cell survival in the absence of None known
survival signal from its netrin ligands
Lung cancer, breast cancer,
many others
Colorectal cancer
Vhl
Forms part of a cytoplasmic destruction
complex with APC that normally inhibits
induction of blood vessel growth when
oxygen is present
von Hippel-Lindau
syndrome
Clear cell renal carcinoma
Caretakers
BRCA1,
Chromosome repair in response to
BRCA2
double-stranded DNA breaks
Familial breast and
ovarian cancer
Breast cancer, ovarian
cancer
MLH1,
MSH2
Hereditary nonpolyposis Colorectal cancer
colon cancer
DCC
VHL
Repair nucleotide mismatches between
strands of DNA
Tumor Suppressor Genes
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The Two-Hit origin of cancer
In all of these syndromes, the second hit is often but not always a
mutation.
Silencing due to epigenetic changes such as DNA methylation,
associated with a closed chromatin configuration and loss of
accessibility of the DNA to transcription factors, is another important,
alternative molecular mechanism for loss of function of a TSG.
Because an alteration in gene function due to methylation is stably
transmitted through mitosis, it behaves like a mutation; because there
is no change in the DNA itself, however, the alteration is referred to as
an epigenetic rather than a genetic change. Epigenetic silencing of
gene expression is a normal phenomenon that explains such widely
diverse phenomena as X inactivation, genomic imprinting, and
regulation of a specialized repertoire of gene expression in the
development and maintenance of differentiation of specific tissues
Retinoblastoma
Retinoblastoma, the prototype of diseases caused by mutation in a
TSG, is a rare malignant tumor of the retina in infants, with an
incidence of about 1 in 20,000 births.
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About 40% of cases of retinoblastoma are of the heritable form, in which the child
inherits one mutant allele at the retinoblastoma locus (RB1) through the germline.
A somatic mutation or other alteration in a single retinal cell leads to loss of function of
the remaining normal allele, thus initiating development of a tumor.
The disorder is inherited as a dominant trait because the large number of primordial
retinoblasts and their rapid rate of proliferation make it very likely that a somatic
mutation will occur in one or more of the more than 106 retinoblasts.
The other 60% of cases of retinoblastoma are nonheritable (sporadic); in these cases,
both RB1 alleles in a single retinal cell have been inactivated independently.
Because two hits in the same cell is a rare event, there is usually only a single clonal
tumor and the retinoblastoma is found in one eye only.
Although sporadic retinoblastoma usually occurs in one place in one eye only, 15% of
patients with unilateral retinoblastoma have the heritable type but by chance develop a
tumor in only one eye.
Retinoblastoma
Hereditary Cancer
Syndromes
Many forms of cancer have a higher incidence in
relatives of patients than in the general population.
There are nearly 50 mendelian hereditary cancer
syndromes.
Hereditary Cancer
Syndromes
1. Breast and ovarian
2. Colon Cancers
3. Li-Fraumeni Syndrome
6. Peutz-Jeghers syndrome
7. Phaeochromocytoma
8. Retinoblastoma
9. von Hippel-Lindau disease
4. Neurofibromatosis
5. Multiple endocrine
neoplasia (MEN)
10. Wilm’s tumour
Familial Breast Cancer
• Population-based studies have shown
that 9% of all women will develop breast
cancer in their life time.
• Most cases of breast cancer are
sporadic. Only 5% to 10% of all breast
cancer cases are hereditary.
Familial Breast Cancer
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Linkage studies in families with early onset FBC led
to discovery of mutations in two genes that increase
susceptibility to breast and ovarian cancer;
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BRCA 1 on chromosome 17q21
BRCA 2 on chromosome 13q12
Together these two loci account for about ½ and 1/3
of autosomal dominant FBC .
Regulation of DNA repair (double strand breaks),
transcription and cell cycle.
RISKS !!!
Female
Male
Breast Ovarian
BRCA1 mutation 40-87% 16-63%
Breast
Prostate
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25%
BRCA2 mutation 28-84%
27%
6-14%
20%
General population 8-10%
1.5%
<0.1%
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Familial Colon Cancer
1.Familial adenomatous
polyposis (FAP)
15% of colon cancers
APC gene (TSG) on chromosome 5q
APC regulates transcription, cell
adhesion, apoptosis and cell
proliferation.
Both alleles of APC must be inactivated
for adenoma formation.
Familial Colon Cancer
2. Hereditary Nonpolyposis Colon Cancer
2-4% of colon cancers
Mutations on 6 DNA mismatch repair genes (MLH1,
MSH2,MSH6, MLH3, PMS1, PMS2)
Both alleles of genes must lose function.
Male heterozygotes for mutant HNPCC genes 90%
lifetime risk for development of colon cancer
Female heterozygotes 70%, but 40% for endometrial
cancer
Li-Fraumeni Syndrome
There are rare "cancer families" in which there is a
striking history of many different forms of cancer
(including several kinds of bone and soft tissue
sarcoma, breast cancer, brain tumors, leukemia, and
adrenocortical carcinoma), affecting a number of family
members at an unusually early age, inherited in an
autosomal dominant pattern.
This highly variable phenotype is known as the LiFraumeni syndrome (LFS).
Li-Fraumeni Syndrome
TP53, encoding the protein p53, is inactivated in
the sporadic forms of many of the cancers found in
LFS, TP53 was considered a candidate for the gene
defective in LFS.
DNA analysis of several families with LFS has now
confirmed this hypothesis; affected members in
more than 70% of families with LFS carry a mutant
form of the TP53 gene as a germline mutation.
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The p53 protein is a DNA-binding protein that
appears to be an important component of the
cellular response to DNA damage.
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p53
suppresses progression through the cell
cycle in response to DNA damage
initiates apoptosis if the damage to the
cell is severe
acts as a tumour suppressor
is a transcription factor and once
activated, it represses transcription of one
set of genes (several of which are
involved in stimulating cell growth) while
stimulating expression of other genes
involved in cell cycle control
Peutz-Jeghers Syndrome
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Peutz-Jeghers syndrome (PJS) is an inherited
condition that puts people at an increased risk for
developing hamartomatous polyps in the digestive
tract, as well as breast, colorectal, and other types of
cancer.
The STK11 gene (also known as the LKB1 gene) is
the only gene that has been linked to PJS so far.
Neurofibromatosis
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Neurofibromatosis (NF) is caused by
mutation in the neurofibromin gene
AKA von Recklinghausen disease ,
Watson disease
An autosomal dominant neurogenetic
disorder
Characterized by the presence of
multiple benign neurofibromas
Affects the bone, the nervous system,
soft tissue, and the skin
Clinical symptoms increase over time
Neurologic problems and malignancy
may develop
Genotype/Phenotype
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Increased concentrations of nerve growth stimulating activity have
been linked with the development of neurofibromatosis
NF-1 is a disorder with variable phenotypic expression
Some patients may mainly have cutaneous expression, and
others may have life-threatening or sever disfigurement
The variation of this disease is even shown within families
The spontaneous mutation rate is 100 times greater than for
many genes, and it is thought to contribute to approximately 3050% of neurofibromatosis cases.
A genotype- phenotype analysis suggests that there is no clear
relationship between specific NF1 mutations and clinical features
of Neurofibromatosis type 1.
Diagnostic criteria for NF-1
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(The diagnostic criteria are met if 2 or more of
the features listed are present.)
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Six or more café au lait macules larger than
5 mm in greatest diameter in prepubertal
individuals and those larger than 15 mm in
greatest diameter in postpubertal individuals
Two or more neurofibromas of any type or 1
plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
Two or more Lisch nodules (iris
hamartomas)
A distinctive osseous lesion, such as
sphenoid dysplasia or thinning of the long
bone cortex, with or without pseudoarthrosis
A first-degree relative with NF-1 according
to the above criteria
Colorectal Cancer
• 11% of cancerrelated deaths
• Tumor
progression may
take 10-35 years
• Adenomatous
polyp develops
into carcinoma