10- Cancer Genetics/ Epigenetics Flashcards
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)
What kind of methylation happens in cancer?
- both global hypomethylation/ selective hypermethylation
- disruption of methylation patterns > silencing of TSs/ ectopic expression of normal genes
- ↑ methylation of TS > silenced/ ↓ methylation of silenced genes
What are the possible scenarios of CpG methylation/ TF interactions in cancer?
- TF binding interferes with CpG methylation
- TF only binds if CpG is methylated
- TF can not bind if CpG is methylated
What is interesting about silenced genes?
- more prone to LOH (loss of heterozygosity)/ mutation
How do histone posttranslational modifications regulate gene expression?
“epigenetic” histone code
- posttranslational modifications of histone proteins modify chromatin structure/ impact gene expression
- acetylation/ deacetylation/ methylation of histone proteins interacts with DNA methylation
- deacetylation of histones converts chromatin to more compact
How do microRNAs regulate gene expression?
- epigenetic silencing of miRs
- miR system = endogenous post-transcriptional mechanism
- target groups of genes rather than single targets
- miRs inhibit production of TFs that express tumor-promoting genes
> loss of miR > overexpression of tumor-promoting genes - overexpression of miR inhibits TS production > pro-carcinogenic
What is the difference between a driver/ passenger gene?
Driver mutation- germline mutations/ transforming somatic mutation
Passenger mutation- accidental/ do not contribute to cancer phenotype
