10- Cancer Genetics/ Epigenetics
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What are the 2 types of tumor suppressor genes/ examples of each?
Gatekeeper gene ex) RB/ APC/ NF1 Caretaker gene ex) TP53
What is a gatekeeper gene?
• TS gene that operates to hinder cell proliferation or further cell differentiation/ cell death > prevents generation of neoplastic cells
What is a caretaker gene?
• TS gene that encodes a protein responsible for maintaining the integrity of the genome > prevents generation of neoplastic cells
What is the main difference between oncogene activation/ TS inactivation?
Oncogene activation = dominant TS inactivation = recessive (need both alleles mutated)
What is a tumor suppressor gene?
• gene whose partial/ complete inactivation leads to ↑ likelihood cancer • gene responsible for constraining cell proliferation
What is an oncogene?
• gene that can transform cells • gene whose activation leads to cancer
Where/ how can TS inactivation occur?
Familial/ Inherited > occurs in germ line Sporadic > in somatic cells
What was the first tumor suppressor discovered?
RB > Retinoblastoma
What was Knudson’s hypothesis?
RB: Knudson’s “two-hit” hypothesis - both alleles of gene need to be inactivated for RB tumors to arise (recessive)
What was interesting about retinoblastoma?
• bilateral cases develop faster/ earlier (suggestive of single mutation) > familial (born with 1 mutant allele/ only need 1 mutation) • unilateral cases develop later in life (suggestive of 2 mutation events)
If the odds of having 2-independent mutations in the same cell are small (10^-12), how were patients getting Rb?
• loss of heterozygosity (LOH) • development in a cell of only 1 version of an allele instead of normal 2
What are the mechanisms of LOH? (loss of heterozygosity) • besides mutation, how can wt Rb alleles be eliminated from genome?
• Mitotic recombination • Gene conversion (copying mutant allele) • Chromosomal non-disjunction (trisomy > could have 2 wt/ 2 mutant) • Gene silencing (transcriptional inactivation • Deletion > development of hemizygosity > only 1 copy of gene
What is FAP/ APC?
• in normal colon, polyps develop with age/ rarely become cancerous • in FAP colon, thousands/ 100% chance of becoming cancerous • FAP arises due to mutation in APC gene (accounts for 1% of CRC) FAP = Familial Adenomatous Polyposis APC = Adenomatous Polyposis Coli = gatekeeper gene
How does APC mutation lead to FAP?
• APC = inhibitor of Wnt signalling • with APC loss > accumulation of B-catenin in cytosol > ↑ Wnt/ B-catenin signalling> ↑ survival/ proliferation
What syndrome is associated with loss of TP53?
Li-Fraumeni
What is NF1?
• loss of neurofibromin > neurofibromatosis (cafe au lait spots) • NF1 = Ras-GAP (switches Ras off) • loss of NF1 > overactive Ras signalling
Why is NF1 not a typical tumor suppressor?
• Knudson’s 2 hit hypothesis: loss of both alleles required for phenotype • NF1+/- cells with 50% functional protein (1 wt allele) show ↑ growth signalling through Ras compared to NF1-/- = Haploinsufficiency- loss of 1 allele sufficient to induce neurofibroma phenotype
Why is sporadic cancer due to mutated proto-oncogenes common but familial cancer due to mutated proto-oncogenes rare?
• embryonic lethality ↑ spontaneous abortions
What is an oncogene familial syndrome?
H-ras > Costello syndrome
What is haploinsufficiency/ how does it change the 2-hit hypothesis?
• loss of 1 allele sufficient to induce phenotype (dominant) • Knudson’s 2 hit hypothesis: loss of both alleles required for phenotype
What are epigenetic changes?
• inherited changes in gene expression that do not depend on alterations of DNA nucleotide sequence > changes in behaviour of cell/ activity state of chromatin
How does DNA methylation occur?
• DNMT enzymes methylate • CpG sequences are targets for cytosine methylation • about 60-70% of gene promoters have CpG islands
How does DNA methylation regulate gene expression?
• DNMT activity methylates CpG sequences in islands > silence gene expression • DNMT activity methylates sequences within gene bodies > prevent spurious initiation of transcription
What are the consequences of DNA methylation?
• methylated CpG islands prevent transcription complex from loading onto DNA > steric inhibition (impediment for transcription) • methylation pattern of DNA affects higher order chromatin structure (via histone modifications)