1/11 Molecular Basis of Cancer 2 - Corbett Flashcards
tumor progression
tendency for tumors to become more aggressive and acquire greater malignant potential over time AND become more resistant to treatment
key component: acquisition of multiple mutations
glioblastoma multiforme
pathogenesis
overproduction of growth factor PDGF
amplification or point mutation in receptor Tyr kinases → malignant transformation
epidermal growth factor receptor
ERBB1 and lung cancer
- point mutations described in adenocarcinoma
- overexpression in squamous cell carcinomas
ERBB2 (HER2/NEU) and breast cancer
- amplified in 25-30% of breast cancers → constitutive kinase activity
mutation of downstream signaling proteins
point mutations of Ras family genes are most common abnormalities involving proto-oncogenes
ex. BRAF V600E in msclc/colorectal/melanoma, tx: vemurafenib
tumor suppressor genes
normal cellular proteins that negatively regulate cell growth
typically, both alleles damaged → transformed phenotype
governors: typically hinder cell proliferation
guardians: sense genomic damage
explanations and common theme:
- retinoblastoma protein
- p53
- adenomatous polyposis coli
- transforming growth factor beta
- retinoblastoma: key negative regulator of G1/S phase transition
- unphosphorylated Rb binds E2F (tf), blocking it from binding DNA → transcription blocked, S phase blocked
- during cell growth, Rb is phosphorylated → E2F released → E2F binds DNA and gene expression occurs → cell cycle progresses
- directly or indirectly INACTIVATED in most cancers
- cytogenetic deletions
- point mutations
- promoter hypermethylation to turn off expression!
- Rb compromised via…LOF mutations, viral inhibition
- results in retinoblastoma (childhood ocular malignancy → leukocoria, strabisumus, uveitis, glaucoma)
explanations and common theme:
- retinoblastoma protein
- p53
- adenomatous polyposis coli
- transforming growth factor beta
- p53: central monitor of stress in cell
- most frequently mutated gene in human cancer
- fx:
- cell cycle arrest: CDKI/p21 transcribed → inhibits cyclin-Cdk, blocks Rb-P
- cell cycle arrest at G1/S checkpoint
- DNA repair or…
- apoptosis
- typically, p53 has short halflife
- MDM2 targets p53 for degradation
- cellular stress? p53 released from MDM2
Li Fraumeni syndrome: cancer predisposition syndrome
- germline mutation in one p53 gene
- autosomal dominant
- 25x incr in cancer risk
effect of DNA viruses
HPV, HBV, EBV can bind p53 and Rb and nullify their protective fx
explanations and common theme:
- retinoblastoma protein
- p53
- adenomatous polyposis coli
- transforming growth factor beta
- adenomatous polyposis coli (APC)
- part of WNT signaling pathway → controls cell fate, adhesion, polarity
- exerts antiproliferative effect by regulating destruction of cytoplasmic protein beta-catenin
- loss of APC → beta catenin accumulation, translocation to nucleus → acts as growth promoting tf
- somatic loss of both APC alleles seen in 70% of sporadic colon cancer
familiar adenomatous polyposis
- auto dom APC gene mutation → inapprop Wnt signaling
- pts develop 100-1000s of polyps in colon by early 20s
- 100% devlops colon cancer at 35-40
explanations and common theme:
- retinoblastoma protein
- p53
- adenomatous polyposis coli
- transforming growth factor beta
- TGFbeta
- potent inhibitor of proliferation in normal cells
- mutations in TGFbeta receptor or SMADs affects transduction of antiproliferative signals
100% pacreatic, 83% colon cancers have at least one component of pathway mutated
4 definitive Lynch Syndrome genes
1. MSH2
2. MLH1
- MSH6
- PMS2
bold account for 90% of patients with Lynch syndrome
mutations in genes involved in DNA mismatch repair → no proofreading →microsatellite instability seen in Lynch syndrome
- familiar carcinoma of colon involving cecum and prox colon, endometrium, other organs
- auto dom
breast cancer genes
BRCA1 and BRCA2
-
tumor suppressor
- repair of dsbs
- transcription
- ubiquitination
gen pop frequency = 1:400
confer 10-30x higher risk
