Test 1: lecture 10 genetics of cancer Flashcards
Self-sufficiency of growth signals
Activating mutations in ____(autonomous growth)
Car Analogy: ____
oncogenes
foot on the accelerator.
Insensitivity to anti-growth signals
Deactivating mutations in ____
Car analogy: ___
tumor suppressor genes
brake is broken.
Limitless replicative potential –
Abnormal/decreased expression of ____ - prevents ___shortening that normally would induce cellular senescence /death.
telomerase
telomere
Evasion of Apoptosis
Mutations in apoptotic genes or over-expression of ____ allow cancer cells to escape apoptosis
anti-apoptotic genes
Angiogenesis
New blood vessel growth to the site of the tumor, allowing
the cells to get oxygen and nutrients
___
Vascular Endothelial Growth Factors (VEGF)
Tissue Invasion and Metastasis
Tumor cells break the ___ and invade the
ECM, spread to distant sites via the blood stream or lymphatics
basement membrane
6 ways cancers have evolved to survive
mutate growth signals → oncogenes
stop anti-growth signals → turn off tumor suppressor genes
prevent telomere shortening → lives forever
prevents cell death → mutate apoptotic genes and increased production of anti-apoptotic genes
increase blood vessels to area → feed itself (VEGF)
Metastasis
what are some extrinsic environmental exposures that cause cancer
gamma
UV light
second hand smoke
chemicals (asbestos)
what are some extrinsic factors that cause cancer
environmental : gamma, UV, smoke, chemicals
Infectious: viruses, ect
what are the 3 etiologies of feline squamous cell carcinoma
80% UV light exposure
53% p53 mutations (mutate tumor suppressor gene)
80% infection with papillomavirus
how do retroviruses cause cancer
retrovirus invades cell
reverse transcribes its viral RNA into pro-viral DNA
invades the nucleus and inserts itself onto the hosts DNA
over takes the host machinery to make proteins for itself
in cancers will insert promotors upstream from genes that will increase cell growth → uncontrolled growth of the cell
activate oncogenes by inserting next to them and driving their expression from powerful viral promoters
retrovirues cause cancer by activating oncogenes through ___. Which means they activate oncogenes by inserting next to them and driving their expression by the ___
insertional mutagenesis
viral promoter
feline T cell lymphoma is caused by viral promotor that mutates MYC to cause uncontrolled proliferation
feline T cell lymphoma is caused by viral promotor that mutates___ to cause uncontrolled proliferation
MYC
how is rous sarcome virus different from other retroviruses
backwards
normally virus will bind to host DNA and take over
in rous- piece of host DNA SRC gene (tyrosine kinase/oncogene) attaches to viruses RNA and leads to uncontrolled growth
what gene is transferred to viral genome in rous sarcoma virus?
SRC gene (tyrosine kinase/ oncogene) → leads to uncontrolled growth
___ Rare recombination event in which part of the viral genome is replaced by a cellular proto-oncogene
rou’s sarcoma virus
transfer of host SRC gene (tyrosine kinase/oncogene) to the virus
what 4 type of genes are involved in cancer
proto-oncogenes → drive cancer
tumor- suppressor genes
apoptosis gene
DNA repair genes
what are some common oncogenes
Growth factor receptor: Ras, EGFR
Transcription factor: Myc, NFKB
Cell cycle regulator: CDK
these are proto-oncogenes that have been mutated to cause unregulated cell growth
only need one mutated copy to get uncontrolled cell growth
c-Kit → mast cell tumor
MYC→ lymphoma
NFKB→ DLBCL
proto-oncogenes that have been mutated are called ___. they cause ___
oncogenes
uncontrolled cell growth
oncogenes are ___ and need how many copies of the mutation to cause uncontrolled cell growth?
dominant
one copy
MYC is a ___
proto-oncogene that is a master transcription factor
regulates genes that control cellular proliferation
when it is mutated causes uncontrolled cell growth
proto- oncogenes can be growth factor receptors (___), transcription factors (____) and cell cycle regulators (____)
EGFR, RAS, cKIT
Myc, NF-kB
CDK, cyclin
EGFR is a ___
growth factor receptor (tyrosine kinase receptor) that sits on the outside of the cell and when triggered will activate intracellular cascade through the G protein and Ras pathway to increase cell growth
when mutated (oncogene) leads to uncontrolled cell growth
CDK is a __
proto-oncogene that controls cell cycle progression from G phase to S phase
oncogene will cause mutation that will cause cell to continuously grow and not stop to allow time for DNA repair
what receptor mutates in mast cell tumor?
cKIT→ tyrosine kinase receptor that usually binds to SCF and dimerizes to trigger proliferation signal in the cell
it can mutate to dimerize without its ligand or can mutate to just send the proliferation signal
c-KIT mutations in common in what cancer type
mast cell tumor
tyrosine kinase receptor that mutates to cause uncontrolled cell growth
Mast cell tumor
c-KIT → tyrosine kinase receptor
what drug targets cKIT and what cancer is it targeting?
palladia (toceranib)
mast cell tumors
tyrosine kinase inhibitor
palladia(toceranib) targets ____
tyrosine kinase inhibitor
cKIT, VEGFR, PDGFR
tumor types: mast cell, sarcomas, carcinomas, melanomas, myeloma
gleevec (imatinib) and Kinavet (masitinib) target
tyrosine kinase inhibitor → cKIT
Mast cell tumors
gleevec → human med
kinavet → not on the market
palladia/ toceranib→ current med used for canine Mast cell tumors
what happens in Burkitts lympoma
chromosomal transmutation of the MYC oncogene from chromosome 8 to chromosome 14
Ig promotor on chromosome 14 will cause Myc to overwork → uncontrolled cell growth
starry sky appearance on histopath of pale macrophages and dark purple lymphocytes (B cells)
similar to DLBCL in dogs
what happens in DLBCL
diffuse large B cell lymphoma
chromosomal transmutation of the MYC oncogene from chromosome 8 to chromosome 14
Ig promotor on chromosome 14 will cause Myc to overwork → uncontrolled cell growth
starry sky appearance on histopath of pale macrophages and dark purple lymphocytes (B cells)
similar to Burkitt’s lymphoma in humans
chronic myelogenous leukemia (CML)
philadelphia chromosome (9:22)
parts of chromosome 9 (Abl) and 22 (Brc) fuse together creating Bcr-ABL tyrosine kinase
cause over production of Abl gene → leads to uncontrolled cell growth
imatinib is a drug that will inhibit BCr-ABL tyrosine kinase from phosphorylating
imatinib
drug to inhibit BCR-ABL found in CML
prevents tyrosine kinase from phosphorylation
(chronic myelogenous leukemia aka philadelphia chromosome 9:22)
How does NF-KB work
master transcription factors that regulate hundreds of
genes involved in cellular proliferation
inactive in the cytoplasm- phosphorylated then into nucleus and cause cell growth, anti-apoptotic genes, cytokines, and chemokines
what are some common tumor suppressor genes
p53, NF1, BRCA, retinoblastoma
for a tumor suppressor gene to cause cancer it needs ___
both alleles need to be mutated → recessive
how does p53 work
stops and tries to fix/repair cell
if it can’t will trigger apoptosis
tumor-suppressor gene → transcription factor that regulates expression of genes that block cell cycle or induce apoptotic cell death
Rb
retinoblastoma
tumor suppressor gene
prevents excessive cell growth by holding E2F which halts cell cycle
NF-1
tumor suppressor gene
inactivates RAS
Mutations in ___ frequently result in its inability to bind to target genes p21, Bax and GADD45
p53 → tumor suppression gene
p21 →stops cell cycle
GADD45→ repair DNA
Bax→ apoptosis
how does Rb work
tumor suppression gene
Rb produces Rb that hold E2F in place and prevents cell cycle
E2F controls the transition from G1 to S phase
how do viruses inactivate p53 and Rb
produce E7 that binds to Rb
E6 binds to p53
inactivates the tumor suppressing genes
Bcl-2
anti-apoptotic gene
blocks the release of cytochrome C from the mitochondria
follicular lymphoma is caused by the translocation of ___
Bcl-2 from chromosome 14 to 18
leads to an increase in the anti-apoptotic gene → cell does not die
(non-hodgkin lymphoma)
greyhounds get ___
goldens get ___
bernese mountain dogs get ___
osteosarcoma
lymphosarcoma
histiocytic sarcoma
VEGF
causes angiogenesis → new vessel growth
thrombospondin and angiostatin cause ___
inhibit angiogenesis
what drug is used for mast cell tumors
palladia (toceranib) block ckit tyrosine kinase receptor
what medicine is used for HSA
copanlisib (aliqopa)
PIK3CA mutations
what treatment for urothelial carcinoma
zelboraf (vemurafenib)
BRAF mutation (RAS pathway)
