Caroline Speed; Week 9 MED1011; Biochemistry
Tumour suppressor genes: can code for adhesion/recognition proteins, some in DNA repair, some stop the cell cycle in G1. In these genes, loss of function leads to cancer, can be inherited or acquired. Requires both copies to be lost for cancer to develop (two hit hypothesis). One copy may confer cell cycle progression advantage, both has significant growth advantage for cancer. If one copy is inherited only one mutation is required for cancer development. Classic examples are p53 and retinoblastoma gene. Rb is rare childhood tumour of the neural precursor cells of the retina, there are both hereditary and sporadic forms of the disease. If hereditary there are tumours in both eyes, mutant allele on chromosome 13 in every cell of the body. Non hereditary has one tumour in one eye, chromosomal changes only in tumour cells. Rb gene is in every cell in the body, acts as a regulator for cell cycle progression, prevents transcriptional activation of a variety of genes, required for the onset of S phase in the cell cycle. Regulates other processes including differentiation, DNA replication and apoptosis. Is also implicated in breast, lung and bladder cancers.
p53 induces cell cycle arrest, senescence, cell differentiation and apoptosis. It contributes to repair following DNA damage, and will induce cell death if damage is severe. A cancer where p53 is lost early in development is skin cancer. Vast majority of human squamous cell carcinomas induced by sun exposure, at least one copy of p53 is lost early in sun damaged skin. p53 mutations are not sufficient to cause skin cancer on their own- accumulation including Ras oncogene is required.
Mismatch repair genes repair DNA, humans have 8. Also follow two-hit hypothesis. Both sporadic and hereditary colorectal cancers have defects in these genes and show widespread alterations in short repeated sequences (microsatellite repeats). HNPCC is loss of mismatch repair. Phenotypes with short repeated sequences are replication error positive or microsatellite instability.