Cancer 3 Flashcards
What are the gatekeepers involved in cell cycle control?
p53, Rb and Nf1
What are the “caretakers” involved in DNA repair?
BRCA1, BRCA2 and mismatch repair genes
What is Knudson’s 2-hit hypothesis?
In order for a cell to become a tumor cell, both its genes must be “hit” / inactivated
What are the epigenetic alterations that can occur to cells?
- Inactivate TSGs
2. Activate oncogenes
Roles of “oncomirs” and TS miRNA?
Oncomirs cause the degradation of mRNA, lowering the expression of TSGs
TS miRNA can become inactive, which activate the oncogenes that would normally be affected by TS miRNA
Glioblastoma
100x expression of miR21, an mRNA
Most common brain tumor
Inherited / hereditary vs sporadic cases
Hereditary = almost always bilateral and earlier onset is seen
Sporadic = usually unilateral and later onset
Retinoblastoma
Mutation of Rb1
High risk of 2nd hit; high penetrance, but not complete
Role of Rb1?
Sequesters E2F; without Rb, E2F would be active, and continue cell cycle proliferation
Li-Fraumeni syndrome
Mutation of p53
Highly variable phenotype, depending on where the 2nd hit occurs
Role of p53
Involved in DNA repair and the induction of apoptosis
If p53 has a loss of fxn, damaged cells survive and proliferate
Neurofibromatosis Type I
Mutation of Nf1
Neurocutaneous and dermatologic lesions
Lisch nodules, cafe au lait spots, plexiform neurofibroma
Role of Nf1?
Nf1 inactivates the Ras proto-oncogene by increasing the GTPase activity of Ras
Mutation in Nf1 leads to continuously active RAS, eventually causing growth and tumor formation
Hereditary breast cancer
Mutation in BRCA 1 and BRCA 2
Familial adenomatous polyposis (FAP)
Mutation in APC
Tons of polyps!
Role of APC
Normally, APC is supposed to bind to beta-catenin, phosphorylating it for degradation
If BC is not phosphorylated, it translocates to the nucleus, binds TFs and activates MYC
Wnt signalling pathway
Wnt binds to ‘frizzled’ and activates ‘dishevelled’
‘Dishevelled’ inhibits the APC complex
Inactive APC = BC phosph -> cell degradation
Active APC = no BC phosph -> cell proliferation
HNPCC
Mutation: TGF beta 2 receptor
TGFb II receptor mutation is secondary to the mismatch repair defect!
Role of PTEN? What happens if PTEN is lost?
PTEN inactivates PKB/AKT and promotes cell death
If PTEN is lost, the cell cycle is not arrested and there is no apoptosis
Role of WT-1? What happens if WT-1 is lost?
WT-1 is involved in renal differentiation
Wilms tumor = peds kidney cx
Xeroderma Pigmentosum
Defect in nucleotide excision repair (NER)
Absorption of UV light -> pyramidine dimers; increased risk of skin cx
Most common defect is excision endonuclease deficiency
Ataxia Telangiectasia
Mutation of ATM
P/W cerebellar ataxia, oculocutaneous telangiectasia
Bloom syndrome
Mutation of BLM (a DNA helicase)
Loss of fxn -> many chromosomal breaks
BLM prevents XS sister chromatid exchanges
Werner syndrome
Mutation in WRN (a DNA helicase and exonuclease)
Involved in unwinding DNA and trimming damaged DNA; important for telomeres
Mutation results in defective homologous recombo and base excision repair
