3. TUMOR
SUPPRESSOR
GENES
• genes which are involved in normal cell
regulation by negatively controlling progression
through the cell cycle
• identified as genes that prevent the onset of
cancer and tumour growth.
more specifically, they have all been found to be
involved in one or more of the following
functions: •inhibition of cell division
•DNA repair
•apoptosis
• many TS genes with various functions have
been identified to date including: p53, pRB,
TGF–β, APC,NF1, NF2,BRCA1, BRCA2
4.
5. RBGENE
Retinoblastoma gene
Location: long arm (q) of
chromosome 13
Codes for nuclear transcription
protein called pRB
Present in every human cell
Exist in both active and inactive
form
7. MUTATED
FORMOF RB
GENE
The mutant form of RB gene is involved in
several tumors mainly retinoblastoma.
It occurs in 2 forms:
Sporadic Retinoblastoma: Both the somatic
mutations in 2 allelles are acquired after
birth
Inherited/Familial Retinoblastoma: All
somatic cell acquire one mutant RB gene
from a carrier parent. Later during life the
other mutational event of second allelle
affecting the somatic cell occurs. This forms
the basis of two-hit hypothesis given by
Knudson in 1971
10. p53
GENE(TP53)
Protector of the genome
Location: short arm (p arm) of chromosome 17.
Normally present in small amounts
Accumulate only after DNA damage.
2 major functions of p53 in normal cell cycle:
i)in blocking mitotic activity: p53 inhibits
cyclins and CDKs and prevents the cell to enter
G1 phase transiently. This time is utilised by
the cell to repair DNA damage.
ii) in promoting apoptosis: p53 directs cells
which cannot be repaired by inbuilt system to
apoptosis by activating apoptosis inducing BAX
gene.
12. MUTATEDp53
GENE
In its mutated form, it ceases to act as
protector or growth suppressor but instead
acts as growth promoter or oncogene
Homozygous loss of p53 gene➡️genetically
damaged and unrepaired cells survive and
proliferate➡️malignant transformation
Eg: cancers of lung , head and neck, colon
and breast.
Mutated p53 is also seen in the sequential
development of cancer from hyperplasia to
carcinoma in situ and into invasive
carcinoma
13. MUTANTp53
GENE
Rarely, both alleles of p53 gene
becomes defective.( Knudson two
hit hypothesis)
This defect predisposes the
individual to develop cancers of
multiple organs ( breast,
bone, brain, sarcomas etc) ➡️ LI
FRAUMENI SYNDROME
15. TRANSFORMING
GROWTH
FACTOR-β(ΤGF-β)
Inhibitor of cell proliferation
Especially in epithelial, endothelial
and haematopoietic cells.
Acts by binding to TGF-β receptor
forming a complex
This complex acts in G1 phase of cell
cycle at 2 levels:
1) Activates CDK inhibitors with
growth inhibitory effect
2) Suppresses growth promoter genes
such as MYC, CDKs and cyclins
17. APCGENEAND
β-CATENIN
PROTEIN
Adenomatous polyposis coli.
Normally inhibitory to mitosis
which takes place by a protein β-
catenin
β-catenin has 2 functions:
1) binds to cytoplasmic E-cadherin
that is involved in intercellular
interactions
2) activates cell proliferation
signalling pathway
18. In colon cancer cells, APC gene is lost
and thus beta catenin fails to get
degraded allowing the cancer cells to
undergo mitosis
Patients born with one mutant APC
gene allelle develop large number of
polyps in colon
Later, loss of second APC gene allelle
occurs and malignant transformation
of one or more polyps develop.
19. OTHER
ONCOGENES
BRCA1 and BRCA2
Breast cancer susceptibility genes
BRCA1 located on chromosome 17
BRCA2- Chromosome13
Women with inherited defect in
BRCA1 have high risk of
developing breast and ovarian
cancer
20. VHL Gene
Located on chromosome 3p
Mutation of this gene results in
activation of genes that promote
angiogenesis, survival and
proliferation.
This causes von Hippel-Lindau
disease which is a rare autosomal
dominant disease characterised by
benign and malignant tumors of
multiple tissues
VHL gene is found inactivated in 60%
cases of renal cell carcinoma
21. WILMS’ TUMOR GENE
WT1 and WT2 located on
chromosome 11
Prevent neoplastic proliferation of
cells in embryonic kidney
Mutant form of WT1 and WT2 seen
in hereditary Wilms’ tumor
22. NEUROFIBROMA (NF) GENE
They prevent proliferation of
Schwann cells
2 mutant forms: NF1 and NF2 –
seen in neurofibromatosis type 1
and type 2