Chapter 5

Cancer Genetics
Nor Isnida
Mestech
Cancer ?
 CANCER- OVERVIEW

1 billion mutated

§
uncontrolled or derived from ‘crab’
in Latin cells > cancer lump
unregulated cell
to reach 1cm in
growth >cancer diameter/ weigh 1g

In 5.5 Malaysian (1/4 Lung

Chinese, 1/5 Indians Breast cancer →
cervical cancer * →nasopharyngeal/
& 1/7 Malays)
National Cancer Registry 2002 report
colorectal nose cancer *
colorectal

Cancer is a large number of complex diseases, up to a

hundred that behave differently depending on the cell
types from which they originate.
 Age of onset


invasiveness
Growth rate
Prognoses & responsive to
treatment

Nerve
Prostate
cells
gland CANCER
intestines Muscle
cell
Rare form
Lung Most
from
prevalent
undividing
actively
cell :
dividing are
differentiated
-
epithelial cell
cell
 DO
Cancer > genetic disease at cellular level not whole body -

Significant development in understanding the cause of cancer?

Realization of cancer as genetic disease

-5¥
Genomic alterations are associated
single-nucleotide chromosome
amplifications deletions
substitutions rearrangements

a-
Cancer is caused by predominantly in somatic cells. Only about
1% of cancers are associated with germ-line mutation’s that
increase a person’s susceptibility to certain types of cancer
• What causes tumors to form?
• What causes some of them to spread?
• Why do some types of tumors tend to be found in
families?
• Is the tendency to develop cancer inherited?
• Do environmental factors contribute to the
development of cancer? In what sense do they
contribute to development and progression of
cancer?
 Why cancer is to be said a
genetic disease but it is said
only about 1% of cancers
have a hereditary
component?

Why cancer is said not a single

disease?
Cancer: A Genetic Disease

Mutations in genes that control cell growth and

division are responsible for cancer
 ←
• Cancer cell share 2 fundamental properties:-
1) Abnormal cell growth & division (cell proliferation)
2) Abnormalities in the normal restrains that keep cells
from spreading and invading other parts of the body
(mestastasis).

e-
3) Do not respond to chemical signals that inhibit cell
-

division
restrain cell from
-

spreading / divide
 Researchers conclude that :-

Virus>oncogene
Environmental agent
Human genome project
Specific gene > specific cancer

↑ Genomic
instability

Abnormal
Mutation
Proto-oncogene/ tumor suppresor gene growth
Multi step process
Abnormal Invading surround metastasis
proliferation tissue
Back to history and new discovery of new
approach in fighting cancer and why
cancer is now considered as genetic
phenomenon in 20 century.
 •  Not inherited > result of somatic mutation
•
• years X
 Risk of cancer Mendelian Pattern > Combination of particular gene variant

20 century • Sequences of mutated genes →affected tissue→unctrl growth→invaded

surround tissues

•
X
•1971: Richard Nixon US president : cancer as genetic phenomenon
: target “war” →radiation , viruses & chemicals
•1976: 1st gene causing cancer
• : carcinogen are also mutagen
• : questions raised > did the genetic changes cause the can
1970th •Answer: Yes, colon & breast cancer follow
Mendelian Trait Pattern

• Search for cancer causing gene in family with the same type of cancer
• Identify part of genome shared by affected individuals> chromosome
aberrations on unique DNA sequence
• Focused on specific genes at identified region
1980 & • * gene →product protein → cell cycle control
1990 • * 100 oncogenes activated & 30 tumor suppresor gene deactivated
• Mutagens: Any 00
agent that causes an increase in
the spontaneous rate of mutation.
00
• Carcinogen: A physical or chemical agent that
)
causes cancer.
C

÷÷÷yen
causes changes In causes cancels

non an
of
.

are callin oqen

are muthgent
 Normal cell
growth/proliferation

Oncogenes: A
gene whose
activity promotes
uncontrolled
Proto-oncogene: proliferation in
=
A gene that eukaryotic cells.
function to Usually a mutant
initiatiate , gene derived
facilitate or from a proto-
maintain cell oncogene
growth and
Tumor Suppressor division.
Genes: A gene
whose product
functions to
suppress
unrestricted cell
division,
particularly of
tumorous growth Cell cycle control
 É
Focuses on :- "
"
*÷
:*
a. wit
'

• Oncogenes ;÷:*
su press
.
• Tumor suppressor gene cell division

• Genetic pathway to cancer (DNA repair / cell

cycle genes)

3 types of cancer genes

 How might a function to
initiate
,

[proto-oncogeneµ facilitates / maintain

growth A division
a gene that has
cell

an essential
function in
normal cells
become
oncogene

?
The genetic changes that convert proto-oncogene fall into 3
main categories: movement of DNA within genome;
amplification of proto-oncogene & point mutations in a
control element or in the proto-oncogene itself.
Cancer causing mutations results from environmental
influences, such as chemical carcinogens, X-rays and
other high-energy radiation and certain viruses.

How virus able to stimulate the formation

of cancer cell? Are oncogenes &
retrovirus related?
Eipstein-Bar virus >Burkitt’s lymphoma

Papillomaviruses *DNA genome* (HPV 16 & 18)> cervical cancer

HTLV-1> type of adult leukemia

Hepatitis B virus

Human herpes virus 8

15% role of virus in human cancer

RETROVIRUS
RETROVIRUS
enzyme ; reverse transcriptase

Integrase
enzyme
DNA RNA protein

• The reverse transcription of RNA to DNA in

retroviruses represents a noteworthy violation of
the central dogma of molecular biology.
Retrovirus life cycle

Retrovirus contain genes encoding products that

stimulate the cell cycle. These product often
interact with tumor-suppressor proteins,
inactivating them. If the host cell survives the
infection, it may lose control of the cell cycle and
begin its journey to carcinogenesis
 ↓RNAp
DNA

MRNA
↓
protein

Retrovirus : small particle that

consist of genetic
Information s few protein
inside the
capsule
and enter

① attach h to the host cell membrane -

to replicate

genetic material
@ virus
copy their to

form many more viwbes

①
?⃝
 cell membrane
steps :
① Retrovirus attaches s enter host cell

② the capsid Tb dissolved 8 start

to break down .

③ Enzyme of retrovirus is released S

RNA nucleic acid of retrovirus

④ reverse transcriptase will bind to

virus RNA & perform reverse transcription

③ viral RNA will be used to build a

molecule of viral DNA .

Envy me breakdown .
⑥ viral DNA of the nuns will enter into the nucleus along

with the en>

ymecintegrnse)
⑦ Integrase will cut open the DNA 7- the host tell

④ the viral nucleic acid will combined Ñ host cell of DNA -

this combination known as pw rims

-
RETROVIRUS
causing cancer

DeactivationTumor suppressor gene

Activation Proto-oncogene

Eg: HIV (human immunodeficiency virus human

HTLV-1 (T-cell leukemia virus)
 Oncogene Proto-oncogene

1 copy of
oncogene
uncontrolled cell growth

sufficient
Dominant activator of

Cellular
transformation

carcinogenesis
Carcinogenesis Eg:
c-ras proto-oncogene mutant
C-ras oncogene
lung bladder
Dominant trait colon fibrosarcoma (connective tissue
marmary teratocarcinoma (cancer contain
prostate  embriyonic cell type)
MUTANT CELLULAR ONCOGENES & CANCER

•Study of human bladder cancer by Robert Weinberg and

colleges using a transfection test
The Philadelphia Chromosome

point mutation, translocation that lead to gene fusion events, translocation that
lead to over expression by placing the proto-oncogene under the inappropriate
transcriptional control of another gene’s promoter and gene amplification . The
chromosome 9;22 translocation which produces Philadelphia chromosome in
CML, results in a fusion of the protein coding sequence of the bcr & abl proto-
oncogene.
A Reciprocal Translocation Involved in Burkitt’s
Lymphoma
 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.
Tumor suppresor gene
 LOH (Loss of heterozygosity)

• “ A gene conversion event is a mitotic recombination that replaces the

non-mutated allele with the mutated allele.

How does LOH happens?

Some DNA repair go awry, correctly detects a different between the two
copies of the RB allele in the cell & decides to fix it, but choose the
mutant allele by mistake as the one use as the template for correcting
the error.

Knudson’s proposed the Two-hit hypothesis

 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.

If someone inherits a mutation that inactivates one copy of

tumor suppresor gene, such that all the cells of the body,
including the retina & other tissues have from the
moment of conception, already sustained the first hit.
This individu is predisposition to cancer.
germline vs sporadic cancer
 Germline versus sporadic cancer

b) sporadic
a) germline

A) In germline cancer, every cell has one gene variant that increases cancer
susceptibility, and a second mutation occurs in a cell of the affected tissue.
This type of predisposition to cancer is a Mendelian trait. B) Sporadic
cancer forms when a dominant mutation occurs in a somatic cell or two
recessive mutations occur in the same gene in the same somatic cell. An
environmental factor, such as exposure to radiation or a chemical, can
cause the somatic mutations that cause cancer.
 control cell division / cell cycle at
4117 stages
:
Tumor suppressor genes

↳ ① P53 TP 53 ① RB mutation
-

of RB Gene
-

① @ PRB -

retinoblastoma ⇒ GI is → cause familial Retinoblastoma

found nuclei
①
in
phosphoprotein can be
Pten @ I
,

ppyb is
cell cycle
stage of
.

at all
of 911 cell type
Wnt- I G- l -
s cell -

i
DNA damage rensponse
=
cycle
↑
protein
prevent passage to s phase checkpoint
protein
↳ will
③ PRB
p53 to
signal the
RBI breast , try & bladder
become actuated ⑨ mutation of ;

Lancer
'

↓
decide either to
repair the

|
damage → turn on
so many diff repair
pathways = nep

= BER

> or cannot be fixed i kill the

cell Stum on apoptosis pathway

 1. RB protoytpe

:[
•
•
€-7
RB mutation /inactivation of RB genes cause familial retinoblastoma
pRB is a phosphoprotein that regulates transit through the cell cycle by
complexing with transcription factors. It controls the G1/S cell-cycle
checkpoint.

E-¥
⑦• pRB found in the nuclei of all cell type at all stages of cell cycle.

④• It activities varies upon cell depending on its phosphorylation state.

④• In normal quiescent cells, the presence of pRB protein prevent

passage into S phase. After mitosis pRB dephosphorylated & each of
-

the daughter cells enter the quiescent of a new cell cycle.

• Most important genes in regulating choices between orderly growth &
differentiation of tissues.
⑥• Somatic mutations of RB genes occur in most type of tumor and
cancer. Eg mutation of RB1 gene: breast; bone; lung & bladder cancer
 pRB controlling the cell cycle checkpoint

Go phase: pRB protein is nonphosphorylated & binds to transcription

factors such as E2F & activate them. Cell is stimulated by growth factor
enter G1 & S phase.
G1 phase: pRB becomes phosphorylated by the CDK4/ cyclin D1 complex
 2) p53

• Is a DNA-binding protein whose expression is induced by DNA damage;

regulates decisions regarding ‘ programmed’ cell death known as
apoptosis.
• “Guardian of the genome” ; cell that undergone malignant transformation,
p53 will make decision to commit apoptosis
• Mutated p53 is above more than 50% reported in all cancer. p53 mutation
has been found in somatic cell except for Li Fraumeni syndrome (germline
condition mutated p53).
• p53 encoded a nuclear protein that acts as a transcription factor,
repressing/ stimulating transcription of more than 50 different genes
• Continuously synthesized but rapidly degraded.
• Increased p53 happes when:-
i) chemical damage to DNA
ii) double strand breaks in DNA induced by ionizing radiation
iii) presence of DNA repair intermediates generated by exposure of cells to
ultraviolet light.
• p53 protein initiate 2 different responses to DNA damage:-
1) arrest of the cell cycle followed by DNA repair
2) Apoptosis / cell death if DNA cannot be repair

• p53 may be a genetic mediator based on mutational analysis &

epidemiological study.
• p53 acts as a transcription factor to activate expression of p21 which
inhibits CDK/G1 cyclin to halt the cell cycle which then activates DNA
repair.
• In normal cells p53 arrest cell cycle at the G1/S; G2/M checkpoint.
Progression of the cell through S phase is arrest by inhibiting cyclin /CDK
complexes & regulating the transcription of other genes involved in the
phases of cell cycle.
•Most mutations in that inactivate p53 are in the DNA-
binding domain (DBD) and impair its ability to bind
enhancer sequences in its target genes.
 3) Neurofibromatosis 1 (NF1)

• Common autosomal inherited syndrome of benign tumor known as

neurofibromas & other benign tumors of the peripheral & central
nervous system
• Caused by mutations in the neurofibromin gene, a GTPase-activating
protein
• Mutation caused inactivation or loss of activity results in failure of
hydrolysis of GTP to GDP.
• GTP is a common second messenger in intracellular signalling
pathway.
 4) Familial adenomatous polyposis

• FAP common account for 1% of all cases of colon cancer.

• The gene causing FAP is known as APC (adenomatous polyposis
coli), a protein with complex role in cell cycle progression &
extracellular communication & matrix attachment.
• APC is commonly mutated in sporadic non-inherited forms of colon
cancer.
 Familial Breast / ovarian cancer

• Account for about 5% of all breast cancer

• Is genetically heterogenous
• Mutation :BRCA1 & BRCA2 loci on chromosome 17 & 13.
• Women inherited mutant BRCA1 & BRCA2 risk of having breast
cancer: 50% - 80% ; ovarian cancer: 25%
• About 2& of all Ashkenazi Jews are heterozygus for 1 of 3 different
mutant allele of BRCA1 / BRCA 2
• Treatment for women inherit a germline mutation is using antiestrogen
therapies (tamoxifen).
 Summary of tumor suppressor gene

• Identified as genes responsible for autosomal dominant

human tumor syndrome
• Recessive at cellular level, means both alleles must be
activated
• Sporadic cases of the germ-line tumor often also show
mutation, especially deletion/ gene conversion events
producing LOH
We know that somatic mutations of proto-
oncogenes & somatic or inherited mutations
of tumor suppressor genes lead to cancer,
but what would happen if rather than
starting with mutation in one of those gene,
you began with a mutation in a gene
responsible for maintaining integrity of the
genome?
 DNA repair/ cell cycle gene

• Somatic mutation of DNA repair & cell cycle control genes lead to
cascade of mutations, eventually hitting proto-oncogene & tumor
suppressor genes responsible for cellular transformation.
• There are two types of genes involve in DNA repair & cell cycle
control:-
i) Set of gene direct involve in repairing DNA
ii) Gene involve in recognizing that DNA damage/ chromosome
abnormalities have occurred in somatic cell
 gene direct involve in repairing DNA

• DNA molecules undergoes physical damage

• Bases are lost from the phophodiester back bone
• Bases becomes chemically modified to carcinogens / reactive
oxygen species
• DNA strand breaks
• Mistakenly insert the wrong bases by DNA polymerase leading to
mismatch
Gene involve in recognizing that DNA damage/
chromosome abnormalities have occurred in
somatic cell
• Detection of DNA damage or chromosome abnormalities will temporarily
halting the cell cycle division cycle until damage can be fix
• Then making an assessment whether should re-enter cell cycle ( 3 main
checkpoint in cell cycle) or apoptosis
 Autosomal Recessive Syndrome Of Defficiency of DNA
repair

A group of DNA repair genes discovered to be involved in hereditary

cancer predisposition syndromes. The study of these genes has
proposed some important links between transcription & DNA repair in:-
• Bloom syndrome
Mutation in a DNA helicase result in an increased frequency of mitotic
sister chromatid exchanges & increase risk in hematopoietic
malignancy
• Xeroderma pigmentosum]
Mutations in various transcirption factors & nucleases
Extreme risk in developing skin cancer
Defect in ‘excision repair”
• Ataxia telangiectasia
Defective in recognizes broken chromosome & participates in a cell cycle
checkpoint to allow time to repair DNA
Increase risk in hematopoietic & other maglinancies

• Heriditary nonpolyposis colorectal cancer (HNPCC)

4 different genes identified, all involve in DNA double strand mismatch
repair
The mismatches are incorrectly made base pairs that results from
misinsertion of the wrong base by DNA polymerase during cellular
replication
Susceptible to colon, GI tract, endometrium & ovary cancer.
 Pathway to Metastatic Colorectal Cancer

Pathway to Androgen-Independent Prostate Cancer

Pathways to Primary and Secondary Glioblastomas
CONCLUSION
Cancer: A Genetic Disease

Mutations in genes that control cell

growth and division are responsible for
cancer.
Cancer occurrence?

Mutation on critical genes

Unregulated growth of cells

Tumor formation
Detachment of tumor Invading surround tissues

Metastasis

A tumor whose cells do not invade surrounding tissues is

benign.
 Characteristics of Cancer Cells
• Unregulated growth
• Formation of masses in cell culture instead of a
monolayer
• Disorganized skeleton
• Synthesis of unusual cell surface proteins
• Aneuploidy
 Evidence of a Genetic Basis for Cancer

• The cancerous state is clonally inherited.

• Some types of viruses can induce the formation of
tumors in experimental animals.
• Cancer can be induced by mutagens.
• Certain types of cancer tend to run in families.
• Certain types of white blood cell cancers are
associated with particular chromosomal
abnormalities.
 Hallmarks of Pathways to Malignant Cancer

1. Cancer cells acquire self-sufficiency in the

signaling processes that stimulate division and
growth.

2. Cancer cells are abnormally insensitive to

signals that inhibit growth.

3. Cancer cells can evade programmed cell death.

 Hallmarks of Pathways to Malignant Cancer

4. Cancer cells acquire limitless replicate potential.

5. Cancer cells develop ways to nourish

themselves by stimulating angiogenesis.

6. Cancer cells acquire the ability to invade other

tissues and colonize them (metastasize).