Date post: | 16-Jul-2015 |
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Health & Medicine |
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These are genes which apply break to the cell
proliferation.
Misnomer: Because, the physiologic function of these
genes is to regulate the cell growth, not to
prevent tumor formation.
Loss of their normal function results in tumor.
Proto-oncogene
Mutation
Oncogene
OncogenicProteins
Protein kinases
Cyclins
Cell CycleG1 S phase
Tumour
Suppressor gene
Loss of Both Alleles
Rb … = Retinoblastoma,
= Osteosarcoma,
= Carcinomas of breast, colon, lung;
p53 … = Most human cancers,
= Li Fraumeni syndrome,
= Multiple carcinomas and sarcomas
WT-1 - Wilm’s tumour,
P16 (INK4a) - Pancreatic, breast, esophageal cancers,
melanoma;
BRCA-1 & 2 – Carcinomas of breast, ovary;
KLF6 - Prostate cancer;
Tumour Suppressor Genes:
NF-1 = Neuroblastomas
= Neurofibromatosis – I
NF-2 = Schwannomas & meningiomas,
= Neurofibromatosis type II
APC = Familial adenomatous polyposis coli/
carcinomas of colon, stomach,
pancreas and melanoma;
Tumour Suppressor Genes:
RbRetinoblastoma Gene
(TUMOUR SUPPRESSOR GENE)
RETINOBLASTOMA:
1 in 20,000 infants and children
60% sporadic
40% Familial
Autosomal dominant trait
Gene is present on chromosome 13q14,
Loss of both alleles leads to
Retinoblastoma (deletions)
Rb (contd…)
Tumor suppressor genes
Have been
theoretically predicted
by Alfred Knudson
in 1971
(Two-hit hypothesis)
Familial retinoblastoma cases - prone for
osteosarcoma and soft tissue sarcomas,
Inactivation noted in
… adenocarcinoma of breast,
… small cell carcinoma of lung,
… bladder carcinoma;
Because, it prevents propagation of genetically
damaged cells.
It arrests the cell cycle if there is genetic damage
and initiates Apoptosis.
It applies emergency breaks when DNA is
damaged.
chromosome 17p13.1,
Seen in > 50 % of human tumours,
(commonest target of genetic alteration)
Seen in almost all types of cancers,
Mostly acquired mutations - somatic cells
Rarely inherited mutation ( 25 fold )
(Li Fraumeni Syndrome)
- multiple tumors
If DNA damage is not repaired successfully,
then normal p53 perhaps
as a last-ditch effort,
sends the cell to the graveyard
by inducing the activation of
apoptosis inducing genes.
5q21,
Loss of both alleles – tumours,
Develop thousands of adenomatous polyps in the colon
(Familial adenomatous polyposis coli),
Develop colon cancer later,
Also causes – 70 to 80% nonfamilial colorectal carcinomas
and sporadic adenomas,
Tumour suppressor genes
All humans are literally swim in the sea of
environmental carcinogenesis.!!
It is not possible to avoid exposure to sunlight
(ionizing radiation), dietary carcinogens, ROS generated in
metabolism.
Genomic Instability—is the person born with defects in
DNA repair mechanisms.
1. Xeroderma pigmentosa
2. Ataxia-telangiectasia (ATM gene)
3. Bloom syndrome/ Fanconi anemia
Defects in DNA repair: