Molecular Basis of Cancer

Dr Paul Pumuye
Biochemistry & Molecular Biology
 Outline
• Definition of cancer

• Biological behavior of cancers

• Genes involved in carcinogenesis

 Cancer

• A group of diseases that result in uncontrolled growth and

proliferation

• Most tumours are not inherited. They arise in somatic cells as a

result to environmental carcinogens.

• 5-10% of cancers is inherited.

• A single mutation usually does not result in cancer.

• Usually several genes that regulate cell growth are mutated before
a cancerous state results.

• Nonlethal genetic damage lies at the heart of carcinogenesis

 Cancer
• All cancers derive from single cells that
have acquired the characteristics of
continually dividing in an unrestrained
manner and invading surrounding tissues.

• Cancer cells behave in this abnormal

manner because of changes in the DNA
sequence of key genes, which are known as
cancer genes. Therefore all cancers are
genetic diseases.

• Cancers are ‘malignant’ forms of the

disease. ‘Benign’ tumours a localised to the
site of origin and encapsulated. Human melanoma cell undergoing cell division
Credit: Paul Smith & Rachel Errington, Wellcome Images
 Cancer information
• One in three people by 70-80 years in the Western world
develop cancer and one in five die of the disease

• There are approximately 200 types of cancer, each with different

causes, symptoms and treatments

• In 2007, 297,991 people were newly diagnosed with cancer in

the UK

• An individual's risk of developing cancer depends on many

factors, including age, lifestyle and genetic make-up

Cancer Research UK
[Link]
The ten leading cancer types for the estimated new cancer cases and deaths by sex in the United States of America, 2013 .
 Mutation
• Germline mutation
– A change in the DNA sequence that can be
inherited from either parent

• Somatic mutation
– A change in the DNA sequence in cells other
than sperm or egg
– The mutation is present in the cancer cell and its
offspring, but not in the patient’s healthy cells
Causes of genetic damage (mutation)
1- Acquired mutations
Environmental agents
a-Carcinogenic chemicals
• Tobacco smoke (cause of 80 to 90 % of lung cancers)
smoking is responsible for ~ 1/3 of all cancer deaths

• Aflatoxin (A potent liver carcinogen produced by

some molds that contaminate improperly stored
grains etc.)
Causes of genetic damage (mutation)
b- Radiation
– Non-ionising radiation - solar ultraviolet radiation major
cause of skin cancer
– Ionizing radiation

c- Viruses
tumor viruses:
– Hepatitis B virus ; liver cancer
(100 fold increased risk of liver cancer)
– papilloma virus ;cervical cancer

2- Inherited mutations
 Consequences of Mutation

DNA Repair Normal cell

Mutation Bypasses repair Mutant cell Cancer

Radiation
Chemicals
Viruses Fails repair Apoptosis
Cancer progression
Diverse experimental approaches are
used to study tumourigenesis
1. Cell culture

2. Tumour transplants

3. Oncogenesis in animals

4. Genetically engineered organisms

5. Molecular analysis
 Density dependent inhibition

Normal cells proliferate in culture until they reach a finite cell density, at which
point they become quiescent. Tumor cells, however, continue to proliferate
independent of cell density.
Normal vs Tumour Development
Biology of tumor growth

Relapse
Hallmarks of Cancer

Weinberg 2000, Cell

Additional Hallmarks

Hannanh and Weinberg, 2011

 Mutations & cancer genes
• Cancer genes are causally implicated in carcinogenesis

• Mutations in cancer genes can occur somatically or can be

inherited.

• Mutations in some cancer genes can be inherited from parents,

in which case they are present in every cell of the body. Such
people are at a higher risk of developing cancer.

• Somatic mutations can occur in any of the cells of the body

except the germ cells (sperm and egg) and therefore are not
passed on to children.
 Cancer and genes
To date, we know of approximately 400 somatic “cancer genes” *
but there are almost certainly more to be found

1. Proto-oncogenes

2. Tumour
suppressor
genes

3. DNA repair
genes

4. Apoptosis genes
Cell growth, Differentiation and Division
Protooncogenes

++
+

CELL Differentiation
++

--
Tumour Suppressor Genes

Growth

Cell Cycle
DNA Repair

Cell Cycle Check points

eg RB1 and p53 TSGs
Apoptosis
Cell Division
 Tumour Suppressor Genes

• Normal genes that function to prevent the

development of neoplasia.

• Tumours tend to develop when both normal

alleles are lost or inactivated.

• Tumour suppressor genes usually have a

recessive effect.
 Tumour Suppressor Genes
• Patients with familial cancers frequently
inherit one normal and one abnormal
tumour suppressor gene from their parents.

• If the second normal allele is lost, the

protective effect of the gene product no
longer exists.
 Tumour Suppressor Genes and
Retinoblastoma
• Retinoblastoma (Rb) is the commonest malignant eye
tumour of childhood.

• 20-30% of cases – both eyes affected.

• All these bilateral cases and 15% of the unilateral cases

are inherited as an autosomal dominant trait.
 Retinoblastoma
• Rb develops when both alleles
of Rb gene are lost or
inactivated.

• In non-inherited cases of Rb 2
separate mutations have to
occur de novo in each copy of
Chr. 13 in a single retinal cell.
 Knudson’s Two-Hit Hypothesis

• The 1st Rb mutation is either familial or non-inherited

Rb is usually a point mutation (nonsense, frameshift,
or splicing errors) which results in a truncated protein
or no protein product.

• the second Rb mutation usually involves loss of Chr. 13

either in whole or part following mitotic non-
disjunction or partial deletion respectively.

• Loss of heterozygosity (LOH).

 Other Tumour Suppressor Genes
• Over 20 tumour suppressor genes.
 p53
• p53 (chr.17) → DNA binding protein → cell cycle, DNA
synthesis and programmed cell death.

• It is lost or inactivated during the development of many

different neoplasms.

• Mutations or loss of the p53 gene appear to be the most

common genetic change in cancer (colon, breast, lung
and brain). 75-80% of colon cancer →LOH (p53).

 In some tumours (especially colon cancer) increased

amount of p53 protein occur and indicates a dominant
negative effect.
 Proto-Oncogenes
• Normal genes that when altered can lead to
neoplasia.

• Proto-oncogenes have an important role in cell

growth and differentiation.

• Mutation – oncogenes (gain of function)

• 100 oncogenes
Oncogenes
Oncogenes Activation
 Philadelphia Chromosome
• Ph chromosome is found in
90% of chronic myeloid
leukemia and its absence
generally indicates a poor
prognosis.

• Found in 10-15% of acute

lymphocyte leukemia and
its presence indicates a
poor prognosis.
 Chromosome Rearrangement & Cancer

• Tumours exhibit multiple chromosome

abnormalities.

• different karyotype abnormalities are often

seen within a single neoplasm.

• As the tumour progresses the karyotype tends

to become more abnormal.
 Cancer cells have altered genomes
Karyotype illustrating structural abnormalities in cancer

Credit : Mira Grigorova and Paul Edwards, Department of Pathology, University of Cambridge, unpublished
Source: [Link]/~pawefish/BreastCellLineDescriptions/[Link]
 DNA Repair
• Inherited defects in DNA repair mechanisms result
in an increased frequency of cancer

BRCA1 and BRCA2 Genes

• Confer susceptibility to breast and ovarian cancer when mutated.
• Both encode multifunctional proteins that play important roles in
genomic stability,
– homologous recombination, and
– double-stranded and transcription- coupled DNA repair.

 The BRCA1 and BRCA2 proteins interact and participate in cell cycle
control.
 Germline mutations are the basis for familial occurrence.
 BRCA1 and BRCA2 Genes
• Confer susceptibility to breast and ovarian cancer when
mutated.

• Both encode multifunctional proteins that play important

roles in genomic stability,
– homologous recombination, and
– double-stranded and transcription- coupled DNA repair.

 The BRCA1 and BRCA2 proteins interact and participate

in cell cycle control.

 Germline mutations are the basis for familial occurrence.

Targeted Therapy
Apoptosis
 Major Steps in Apoptosis

‘bubble”

Necrosis= injury
Apoptosis= program for cell death
 APOPTOSIS- programmed cell death
• Normal process
– Spaces between fingers and toes in embryonal
development

– Sloughing off of uterine lining in Menstruation

– Formation of synapses in CNS

– Control of T cells (to prevent autoimmune disease)

 APOPTOSIS- programmed cell death
• Destroy cells that represent a threat
• Virus infected cells
• Immune system cells
• Cells with DNA damage
 APOPTOSIS- programmed cell death
• Signals
– Pro-apoptosis activating “death receptors”
• Fas (natural Killer cells and T cells circulating cytokines,)
• Tumour Necrosis Factor TNF
– Anti apoptosis producing survival factors

• Control genes
– Pro- apoptosis genes
– Anti-apoptosis genes Bcl 2

• Effector mechanisms
– Caspases
• Receptor mediated
• Via p53 gene
• others
 Extrinsic pathway • Binding of Fas by FasL
induces recruitment of FADD
to the cytoplasmic tail of Fas
• The opposite end of FADD
contains a death effector
domain (hatched boxes);
Intrinsic pathway recruitment of either
procaspase-8 or c-FLIP
• Caspase-8 can cleave Bid
• truncated Bid (tBid) can
inactivate Bcl-2 in the
mitochondrial membrane.
• This allows the escape of
cytochrome c, which clusters
with Apaf-1 and caspase-9 in
the presence of dATP to
activate caspase-9.
• Smac/DIABLO is also released
from the mitochondria and
inactivates inhibitors of
apoptosis (IAPs).
• breakdown of several
cytoskeletal proteins and
degradation of the inhibitor of
caspase-activated DNase
(ICAD).
 Summary
• Cancer- group of disorder that evade normal
cellular controls mechanism

• Mutations – Acquired (Viral, chemical, radiation)

or inherited

• Cancer genetic disease (TS genes, proto-

oncogenes, DNA repair genes, Apoptosis genes)

• Apoptosis – programed cell death

Thank you