Neoplasia V Flashcards
What is the function of the APC gene, and what are the cancers associated with it?
Function = prevents nuclear transcription by binding to Beta-catenin
CA= familial polyposis coli
What is the function of the BRCA-1/2 genes, and what are the cancers associated with it?
Function = Regulates DNA repair
CA= breast/ovarian CA
What is the function of the Rb gene, and what are the two cancers associated with it?
Inhibits G1 to S phase
Retinoblastoma
Osteogenic sarcoma
What is the function of the TGF-beta gene, and what are the cancers associated with it?
Inhibits G1 to S phase
Pancreatic and colorectal gene
What is the function of the WT-1/WT-2 gene, and what are the cancers associated with it?
Regulates nuclear transcription
Wilms tumor
Beck-wiedemann syndrome
What is the WNT signalling pathway?
Controls cell fate, adhesion, and polariry during embryonic development
the APC gene and beta-catenin gene are involved in what pathway?
WNT
What is the function of APC protein in the WNT pathway?
Down regulates Beta-catenin to prevent its accumulation
What happens in the WNT pathway when WNT binds?
Inactivation of the APC, leading to increase beta-catenin levels
What does beta-catenin bind to?
TCF factor in the DNA
What type of CA does beta-catenin upregulation lead to?
FAP
What are the three CAs that are associated with the Rb gene?
Retinoblastoma
Osteosarcoma
Soft tissue sarcoma
What percent of Rb dysfunctions are familial? Sporadic?
60% sporadic
40% familial
What is Knudson’s two hit hypothesis?
Both alleles of Rb must be inactivated/mutated for CA to develop
Where does the “second hit” occur in familial Retinoblastoma?
Retinal cells (first in somatic cells)
True or false: Heterozygous Rb genes form CA
False–need homozygous
What is the function of the p53 gene? Associated CAs?
function = inhibits G1 to S phase, repairs DNA, activates BAX
Lung, colon, breast CA
What is Li-Fraumeni syndrome?
CA caused by inactivation of p53
What is the specific pro-apoptotic protein that p53 activates?
BAX
p53 arrests the cell cycle at which phase? How?
G1/S phase
Acts via p21 (cyclin CDK4 inhibition)
What is the function of p21?
G1 arrest (cyclin CDK4 inhibition)
What is the function of GADD45 that p53 upregulates?
DNA repair mechanism
What happens to p53 in tumors?
Inactivated (mutated)
What is the function of HPV E6 protein?
inhibits p53
What is the function of HPV E7 protein?
inhibit p21 and Rb-E2F
What is the function of VHL? What chromosome is it one?
Anti tumor gene on chr 3.
Part of the ubiquitin ligase complex that regulates the HIF-1alpha transcription
What are the CAs associated with VHL mutations?
Hereditary renal cells carcinomas
Pheochromocytomas
Hemangioblastomas of CNS
What is Warburg effect?
Even in presence of ample O2, CA cells demonstrate a distinct form of metabolism characterized by high levels of glucose uptake and increased concentration of glucose to lactose via the glycolytic pathway
What is the basis for PET scans?
Tumors like Glucose (Warburg effect) Thus can label glucose
True or false: Carcinogenesis occurs in a single step
False–multistep process and accumulation of mutations
How long does telomerase last in normal cells? Then what happens (normally)?
60-70 doublings, then p53 activated
What is the function of telomerase in CA development?
Maintains telomere length
DNA methylation upregulates or downregulate gene expression? How?
Downregulates– condenses chromosome
What are miRNAs?
family of 19-24 nucleotides that regulate mRNA function at the posttranscriptional level
What percent of cancer are the result of chemical carcinogens?
80-90%
What are chemical carcinogens?
highly reactive electrophiles that remove electron from DNA
What does it mean when a carcinogen has a “direct action” effect?
Act without modification
What does it mean when a carcinogen has an “indirect action” effect?
Require metabolic activation
What is the relationship between promoters and initiators?
Promoter given after initiator, and in a short time frame, is associated with CA development
What are initiators
Chemical that initiate carcinogenesis, and produce cell alteration
Not sufficient for tumor formation
What are promoters?
Induces tumors in initiated cells
Non-tumorigenic by themselves
What are polycyclic aromatic hydrocarbons?
Products of combustion
Associated with lung and bladder CAs
What type of CAs are associated with aromatic amines and Azo dyes? MOA?
liver CA
action of p450 cytochrome oxygenase system
What is beta-naphthylamine? What CA is it associated with?
Material used in rubber industry
Bladder CA
What is Aflatoxin B1?
Carcinogenic mycotoxin produced by aspergillus flavus in corn/peanuts
What is the effect of Aflatoxin B1?
Hepatocellular carcinoma d/t p53 mutation
What is the MOA of Nitrosamines and amines
Formed in Gut of humans, associated with gastric carcinoma
Asbestos is associated with what CAs?
Mesothelioma (but lung CA more often)
Chromium, nickel associated with what CAs?
lung CA
Arsenic is associated with what type of CA?
Skin CA
What is the effect of estrogen in carcinogenesis? What CA is this associated with?
Promoter of chemical carcinogenesis
Liver CA
What is the effect of diethyl-stilbesterol?
Promoter of Postmenopausal endometrial CA
What is the MOA of high fat diet?
Increased bile acid production
Colon CAs
What are the molecules associated in the WNT pathway, and how do they lead to CA?
WNT receptor inhibits APC from inhibiting Beta catenin.
If there is no APC d/t mutation, then FAP
p53 acts through what other p# molecule to inhibit CDK4/cyclin
P21
What is the MOA of direct carcinogens? Indirect?
Direct = React with DNA Indirect = usually metabolized by p450