In cancer TSGs are usually things that negatively regulate the cell cycle preventing growth and delaying division in order to ensure that there is genomic integrity even after genotoxic stress that could be caused by things such as oxygen radicals and carcinogens.
p53 causes apoptosis when there is DNA damage to prevent a damaged cell from replicating. It causes a deregulation of cell growth in order for repair to take place. This is vital in tumours as these things are downregulated so that the tumour develops without these mechanisms suppressing it. The cells can then grow and proliferate in a deregulated manner. Tumour suppressor genes are seen in a 'recessive' pattern in cancer- the mutated cell will have an effect on the cell in a dominant manner- however, until both genes are mutated there will not be deregulation to the point of tumorigenesis. If one is 'knocked out' the other compensates for the regulatory function.
If one mutated allele is inherited, only one needs to be mutated sporadically so in these cases there is usually earlier onset of disease.
TSGs:
p53 - Li Fraumeni Syndrome
RB1 - Retinoblastoma
BRCA1 - Breast cancer
BRCA2 - Fanconi anaemia
APC - Familial Adenomatous polyposis
CHK2 - Li Fraumeni
ATM - ataxia talengesia
VHL - Von hippel landau (phaechromocytoma/ renal carcinoma)
Retinoblastoma is a cancer of the retina, and if RB1 is mutated. 40% of this is familial and will affect both eyes giving a squint and a white reflection. Treatment is lazer therapy or chemotherapy. Around 90% are cured. In familial cases 20% have large mutations in the gene though single base changes account for some cases. RB1 tends to be hypermethylated.
In familial RB there are many people affected in a family.
The RB gene usually functions as a transcription repressor so it usually sits on part of the DNA blocking the transcription. However, in G1 phase it is phosphorylated by cdk4/6 which causes it to uncouple from the DNA, cdk2 and cyclin e also phosphorylate the RB protein at the end of G1 allowing proliferation.
p53 is the most common TSG mutated in cancer. It is considered the 'guardian of the genome'. It protects against the genomic instability. Around 40% of all human cancers carry this defect- it may be much higher than this. Genetically and clinically it presents with 'Li Fraumeni'- there are early onsets of tumours and there are multiple primary tumours. In a family tree many members would be affected. Around 400 families worldwide are affected.
There are different types of Li Fraumeni Syndrome.
LF1 - 70% - mutations in germline p53 on chromosome 17. Sarcomas develop before age 45 and there is usually at least one primary relative with a cancer under the age of 45.
LF2 - p53 (40%) or CHK2 mutations - very early onset. Childhood cancer or brain tumour before 45. Primary or secondary relative with linked cancer.
LF3 - chromosome 1
p53 mutations can lead to cancers of the ovary, oesophagus, lung, head and neck... etc. It is widespread. Loss of p53 usually comes directly before the tumour develops, it's often the last mutation that causes a hyperplastic area and adenoma to become a carcinoma. Carcinomas can invade and metastasise.
The p53 TSG is a tetramer and transcribes proteins that stop the cell cycle. This is usually mediated by ATM and CHK2. These genes usually cause activation of p53 which then causes a feedback loop to mdm2 which inhibits the activation of p53. This is the 'master switch'. p53 can cause apoptosis through the activation of BCL2. When there's cellular stress p53 accumulates and upregulates this protein which causes the cell death. Mutant p53 can't transcribe the molecules that cause cellular senescence, apoptosis, growth arrest and inhibiting angiogenesis. Gain of function mutants have increased drug resistance and these do actually promote genomic instability.
BRCA1 and BRCA2 are indicated in breast carcinoma and ovarian tumours. Around 1 in 100 women have BRCA1 mutations and it accounts for over 60% of inherited breast cancer. Of all breast cancers it is around 5%.
BRCA1 mutation is also associated in prostate cancer. Around 300 different mutations have been described- one is a founder gene in the Ashkenazi jewish population. This gene usually function in DNA damage checkpoint signalling so is involved in the repair process of damaged DNA. BRCA1 can be acted upon by ATM and CHK2 and acts during G2 phase or S phase. In these phases it can cause cell cycle arrest so DNA can be repaired. BRCA2 predisposes to the same tumours as BRCA1 but also has a role in fanconi anaemia. These genes are not very often indicated in breast cancer that is not familial.
BRCA 1 tumours have a higher mitotic rate, BRCA2 tumours have higher tubule formation.
BRCA2 acts with RAD51 in Homologous recombination repair. It is loaded onto the DNA and helps nucleotide filament formation. The major role is to modulate DNA double stranded break repair.
BRCA1 forms an anchor so that RAD50 can act in repair.