Molecular oncogenesis Flashcards
Genes whose normal function is to REDUCE genomic instability
Tumor supressors
Functions normally to SLOW cell growth (and/or repair DNA). Thus tumor cells want these genes INACTIVATED
Tumor supressors
Oncogenes
Genes which, when activated (by mutation, virus etc.), increase the propensity for genomic instability
Functions normally to PROMOTE cell growth. Thus cancer wants these genes ACTIVATED.
Oncogenes
Testing for tumor suppressor mutation
Test must assay global gene function. PCR for microsatellite instability or be prepared to find nearly any possible mutation. Full gene sequencing
IN GENERAL, BOTH COPIES OF A ______________ MUST BE INACTIVATED FOR A CANCER CELL TO BENEFIT!
Tumor suppressor (mutations that activate tumor suppressors do not cause cancer)
Testing for oncogene mutations
Global function testing, targeted PCR or sequencing
Difficult for cancer to make a better version of oncogenes so cancer makes mutations that _______ oncogenes.
up-regulate oncogenes
Oncogenes: High peak on 4-D graph=
strong advantage for cancer cell (up-regulate oncogenes)
Tumor suppressors: Valley on 4-D graph=
strong advantage for cancer cell (down-regulate tumor suppressors)
True or false? You will never see cancers with mutations that inactivate (valleys) oncogenes.
True
single most most common genetic alteration in human tumors?
p53 tumor suppressor (over 50% have mutation)
p53 function
- regulates G1–>S
- cell cycle arrest
- triggers apoptosis
p53 mutation 80% are what kind of mutation and where?
point mutation on DNA binding region (this is an example of MICRO instability)
Interference with protein function creating a functional (but not QUANTITATIVE) deficiency. Name an example of actual quantitative deficiency.
E6 protein of HPV binds p53 and promotes degradation.
NOTE: remember it is E7 of HPV that binds to and inactivates RB for increased G1–>S phase transition
Li-Fraumeni Syndrome:
- Knudson’s Two Hit Hypothesis (just like RB)
- One inherited INACTIVATING mutation in p53
- Acquired second hit in only good copy of p53 triggers the actual tumor
Li-Fraumeni Syndrome: Predisposes individual to what?
-Tumors at a young age (
APC (Adenomatous polyposis coli) gene
- Tumor suppressor gene
- Down-regulate growth-promoting signal of B-catenin!
Familial adenomatous polyposis (FAP)
- One defective germ-line mutation of APC
- Thousands of colon polyps
- Cancer with second APC gene mutation
Sporadic colon cancer: 70-80% homozygous loss of what gene?
APC
Functions of Beta-Catenin
- Enters nucleus and up-regulates cell cycle genes
- Attached to E-CADHERIN
