05 - Cancer Flashcards
Name 3x Tumour Suppressor Genes and describe the cancer associated with them
1 - RB1
- controls cell cycle arrest. When phosphorylated, Rb1 binds to E2F, inhibiting the role of E2F as a transcription factor
- loss of RB1 = Retinoblastoma
2 - p53
- at the centre of signalling network of cell cycle control
- p53 is activated upon cellular stress. It becomes phosphorylated which means it can escape repression by MDM2. Acts as a TF = cell cycle arrest
- Familial mutations ass. with Li-Fraumeni Syndrome
3 - CDKN2A
- encodes 2 genes:
- P16 INKA - which inhibits CDK4/6, which keeps Rb1 phosphorylated and thus = cell cycle arrest
- P14 ARF - which destabilises MDM off p53 = cell cycle arrest
What are the 5 types of oncogenes
1 - Secreted Growth Factors 2 - Growth Factor Receptors 3 - Signal Transducers 4 - Inhibitors of apoptosis 5 - Transcription Factors
Provide an example of a Secreted Growth Factor Oncogene
> SIS gene
> encodes protein similar to PDGF = activates cell proliferation
Provide an example of a Growth Factor Receptors Oncogene
> EGFR
> NSCLC
Provide an example of a Signal Transducers Oncogene
> PI3Ks - family of protein kinases
phosphorylate Inositol containing lipids:
PIP + P = PIP2 + P = PIP3
PI3k pathway deregulated in most cancers
GoF mutations
Provide an example of a Oncogene which inhibitors apoptosis
> BCL2 gene
overexpression of BCL2 gene associated with Follicular lymphoma
t(14;18) BCL2/IgG locus
Provide an example of a Transcription Factor Oncogene
> EWS/FLI1 fusion in Ewing Sarcoma acts as a TF
What domain are mutations found in EGFR in NSCLC?
Tyrosine Kinase domain - encoded by exons 18, 19 and 21
what is the common drug resistant mutation in EGFR
Thr790Met
What type of receptors to PI3Ks transduce signals from
RTKs - receptor tyrosine kinases
What type of receptors does the RAS signalling pathway transduce signals from
G-protein coupled receptors
Describe 4 mechanisms/mutations which occur in oncogenes to drive malignancy
1) GoF point mutations
- BRAF V600E results in signalling pathway constitutively active = malignant melanoma
2) Amplification
- HER2 - human epidermal growth factor receptor 2
- expressed on breast cell surface but increased copy no. on breast cancer cells = cell hypersensitive to growth factors
3) Translocations creating novel Gene fusion
- BCR-ABL1 = tyrosine kinase activity (constitutively active)
4) Translocation of oncogene into a transcriptionally active region (e.g. Ig locus).
- Burkitt Lymphoma, t(8;14) - MYC gene into Ig locus
What is the testing pathway of Lynch Syndrome referrals
> Tumour tissue is 1st sent for IHC testing - to look for levels of the MMR protein.
> If Loss of MMR protein detected and is MLH1 = MLH1 hypermethylation testing (15% sporadic cancers)
> if NO evidence of MMR protein loss = proceed with MSI studies
> no mutations - proceed with Germline mutation testing
Tumour Suppressor genes can be categorised as:
GATEKEEPERS
- control cell cycle
- RB1, p53, APC
CARETAKERS
- maintain & protect integruity of genome
- MLH1, MSH2, MSH6
What types of mutations tend to be associated with TSG
Loss of function or Inactivation of TSG
Tell me about Retinoblastoma
- Mutations in RB1 gene
- aggressive childhood cancer or eye
- can be unilateral (sporadic) or bilateral (using familial - often has a gremlin mutation)
- presenting sign is leukocoria - white pupils on photos
- tumours often show LOH
- hypermethylation of promoter seen in 10% tumours
- LoF mutations = almost complete penetrance
p53 is activated in response to _________
cellular stress (genotoxic or non-genotoxic)
in normal cells, p53 levels are kept low, how
The E3 ubiquitin ligase MDM2 degrades p53 protein.
p53 activates MDM2 expression
positive feedback loop to maintain low p53 expression
Under cellular stress conditions, p53 is ________
Phosphorylated & acetylated.
MDM2 can no longer interact and degrade p53 = increased levels of p53 - acts as TF to express downstream targets
what proportional of colorectal cancers are associated with Lynch syndrome
3.5%
Lynch is also known as ________
Hereditary non-polyposis colorectal cancer (HNPCC)
What is the inheritance of HNPCC
AD. But AR at cellular levels - needs both alleles to be affected (2-hit hypothesis)
What genes are involved in HNPCC. What proportions
> 80-90% mutations in MLH1 and MSH2
7-10% in MSH6
< 1% in PMS2
3% due to deletions in 3’ end of EPCAM (upstream of MSH2)
Tell me about FAP
Familial Adenomatous Polyposis
- most common polyposis syndrome
- APC gene (TSG)
- AD
- characterised by 100-1000s of adenomatous colonic polyps during 2nd decade of life
- almost 100% risk of developing colorectal cancer if NOT treated (colorectomy)
- colonoscopy screening occurs from age 10yr if have an APC mutation
- mostly LOF
