Download Discuss the assertion that cancer is a disease of damaged genes?

Discuss the assertion that cancer is a disease of damaged genes? (Plan)
Intro:
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Cancer=heritable loss of control of cell cycle=excessive production of cells=tumour formation.
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Rare considering high rate of cell divisions (10^16 in human lifetime): genetic/cellular control of
division: 10^-6 natural mutations= 10^10 per gene in lifetime.
Oncogene: when mutated promotes tumour formation.
Tumour supressor
Microevolution (mutation, enviro selection, inherited background)
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Microevolution:
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Oesophageal cancer: model for microevolution
mutation of P53 (transcription factor) gene:from low levels and unstable to stable.
Tetramer: just 1 mutant disrupts function: complex can't bind to DNA, transcription of DNA
repair proteins inhibited.
Subsequent mutations or chromosome instability (CIN: translocation)=abnormal cells.
1-2mm: oxygen and nutrient limiting factor, selection for subsequent mutants to overcome sel
pressures.
Enviro: alcohol: ethanol metabolised to acetaldehyde, can cause mutations. Enviro selects
mutant cells.
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Inherited ALDH2* mutation in aldehyde dehydrogenase (usually detoxifies acetaldehyde).
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Begins with a mutation of P53 gene (disease of damaged gene) other mutations can cause
cancer: oncogenes.
Oncogenes:
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Mutated/overexpressed genes eg Epidermal growth Factor receptor (EGFR) =oncogenes.
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3 ways oncogenes arise: 1: Specific point mutation in tyrosine kinase domain (p loop) of EGFR,
behaves like bound to ligand=cell proliferation=lung cancer. Mutation=disease of damaged gene.
2: Overexpression ( may not be due to damage, simply increase in transcription factor N-MYC or
cyclin D) 3: Translocations (bringing 2 genes together=damaged DNA, intact genes). Eg. Bcr+Abl
frame fusion when chromosome 9/22 fuse in chronic myeloid leukemia. = Excessively active Abl
tyrosine kinase, inhibitors=remission (confirms BCR-ABL is driver mutation).
Oncogenes are highly expressed in cancer cells, conversely tumour repressor genes can be
inhibited in cancer cells.
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Tumour suppressor genes:
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Prevent tumour formation eg Rb gene in retinoblastoma cancer.
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Rb inhibits E2F1 (usually transcription factor for genes which facilitate G1/S transition)
Loss of heterozygosity: children inherit 1 mutated Rb gene= higher risk of retinoblastoma as
single active Rb gene.
Inheritability reflects microevolution=damaged genes.
However as well as accumulation of mutations, epigenetic silencing of tumour repressor
genes=no damage of genes.
Heterochromatin (condensed interphase chromatin which can't be expressed) formation from
histone modification.
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Could be damage of genes for enzymes which modify histones (eg histone methyltransferase).
Viruses:
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Human papillomavirus (HPV):cervical cancer.
E6+E7 transformation genes, first genes expressed.
E6= degrades p53 (a cell cycle repressor / apoptosis activator when DNA is damaged). Also
triggers telomerase (reset bio clock of cell).
E7= binds and inhibits Rb, a tumour suppressor.
Virus hasn't damaged genes.
High rate of cell division= increased chance of further mutation and developing into cancer
tumour.
Conclusion:
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Genes damaged by: point mutations, deletions, CIN, translocation, amplification.
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As well as mutations increasing proliferation, gene damage can lead to angiogenesis (create new
blood supply), invasion of other tissues, Metastasis (entering blood/lymph vessels to spread).
Understanding mutations key to new treatments.
Mutation key to start of microevolution, even if later modifications don't involve genetic
damage.
For cancer causing viruses, further mutations of genome needed after inhibition of P53 and Rb.
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