Tumour suppressor genes

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;

P53

GUARDIAN OF THE GENOME

“Molecular policeman”

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: