Tumor Oncogenesis Flashcards
1
Q
What 3 things are the molecular basis for cancer
A
- acquired mutations (somatic)
- inherited mutations (germline)
- other (infections, epigenetics)
NOnlethal genetic damage lies at the heart of carcinogenesis
2
Q
Mutation + Cancer gene=_______
A
initiating event
most mutations occur randomly and are clinically insignificant
the genme is very big and cancer genes are a fraction of the genome
3
Q
Describe the basic molecular pathology of cancer
A
genetic variants in DNA and RNA lead to diagnosis prognosis and treatment
4
Q
What are oncognenes?
A
- one mutant gene (domniant)
- constitutive activation (fuel)
- growth factors and receptors
- signaling molecules
- transcription factors
- “Driver mutation”
5
Q
What are tumor suppressor genes?
A
two mutated genes (recessive)
loss of function
tumor supressors
cell cycle controllers
*loss of control on roliferation and loss of DNA damage response
loss of heterozygosity
6
Q
Genetic lesions=____________
A
Variants!
7
Q
What are small genetic lesions and what do they cause?
A
- single nucleuotide variant
- insertion/deletion (indel)
- simple to detect
*
8
Q
What are large genetic lesions and what do they lead to
A
- copy number variants, structural variants
- complex to detect
9
Q
What simple genetic lesions occur at the nucleotide level?
A
single nucleotide variant
insertions or deletions “indels”
**these are small/simple genetic lesions**
10
Q
WHat is a single nucleotide variant?
A
- change the codon sequence
- may alter the amino acid in protein
- may contribute to the cancer phenotype
*
11
Q
What are 4 classes of a single nucleotide variant
A
- no mutation
- silent mutation: clinically benign, not reported
-
missense: benign, uncertain or pathogenic
- MD determines if reported
- Nonsense mutation: pathogenic, reported
12
Q
What genetic variations occur at the structural level (chromosomes)
A
large/complex genetic abberations
- fusion genes and chimeric proteins (SV)
- gains and losses of chromatin
13
Q
what are the “driver mutations”
A
- mutations that alter the function of cancer genese
- primarily responsible for the cancer phenotype
- represent therapeutic targets
14
Q
WHat are passenger mutations?
A
- acquired mutation that does not contribute to cancer phenotype
- may synergize with driver mutations
15
Q
Tumors can synthesize and secrete their own ______
A
growth factor! this is called a paracrine loop
- Glioblastoma: synthesis PDGF and PDGFR
- Sarcoma: TGFa and TGFaR
16
Q
What is function and activity of growth factor and growth factor receptor?
What happens when they are mutated?
A
Growth factor receptors are RTKs that, upon GF binding, dimerize and cause the catalytic domain to come together to form a docking site for intracellular mediators.
Normal receptors: transient activation
Mutant receptors: constituitively activated
Overexpression of recptors causes increased sensisitivy to growth factors
17
Q
What are two growth factor receptors that are examples of targeted drug therapy? What drugs target each?
A
ErbB1 (EGFR)
- overexpressed (many cancer)
- mutated (lung cancer)
- predicts responsiveness to anti-EGFR TKI
- Erlotinib
ErbB2 (her2/Neu)
- amplification in berast CA
- poor prognostic sign
- predicts lack of response to estorgen therapy
- Trastuzumab
18
Q
Other than ErbB1 and ErbB2 growth factors what is another growth factor mutation? and where is this commonly seen?
A
KIT mutation
gastrointestinal stromal tumors (GIST)
19
Q
how do we treat a KIT mutation?
A
CKIT tyrosine kinase inhibitor
drug name: Imatinib (Gleevec)
20
Q
Mutations don’t need to be directly in DNA they can be in ________
A
signal transducing proteins
21
Q
what are signal transducing proteins and what are two examples that are commonly mutated
A
- couple receptor to nuclear targets
- mutations “short circuit” receptor
- cancer=constitutive signaling
- ex: RAS, BRAF
22
Q
what is RAS, what does mutation cause?
A
RAS is GTP-binding proteins
mutations affect GTP binding or GTP hydrolysis
Lock RAS in permanent activation: oncogene
23
Q
What is BRAF? WHat kind of cancers result when mutated?
A
serine/threonin protein kinase
hairy cell leukemias
melanomas
24
Q
what drugs are used to treat cancer caused by a BRAF mutation?
A
Vemurafenib
Dabrafenib
25
WHat is a philadelphia chromosome fusion oncoprotein? What causes this?
* cytosolic tyrosine kinase that gets fused to bcr. bcr is a promotr. this fusion leads to actiavtion of everything downstream of the promotor. (loss of regulatory control/constituitively active)
* bcr-abl t(9;22)
26
what cancers are associated with a philadelphia chromosome fusion oncogene? WHat is the treatment
* ABL non-receptor tyrosine kinase
* Chronic myelogenous leukemia
* Acute lymphoblastic leukemia
* treatment: Imatinib (Gleevec) it is the poster child for this therapy bc it was caused by a single gene mutation "oncogene addiction"
27
what is oncogene addiction
when a cancer is caused by a single mutation in a single gene and treating that one mutation cures the cancer ex: philadelphia chromosome, why it is great for imatinib treatment
28
What influence do oncogenes have on transcription factors? what are some examples?
* TFs are the endpoint of signal transduction
* oncogenes lead to continuous stimulation of TFs which drives expression of growth promoting genes
* ex: MYC, MYB, JUN, FOS, REL
29
What is Myc? What results from activation of MYC gene
Myc is a master transcriptional regulator of cell growth.
mutations lead to:
1. upregulation of Cyclin D (cell cycle progression)
2. other pro-growth genes that allow cells to divide uncontrollably
30
WHat type of cancer is associated with Myc mutations?
Burkitt Lymphoma
31
What are the cell cycle regulators?
* Cyclin dependent kinases (CDKs) 4, 2, 2, 1
* constituitively expressed
* phosphorylate target proteins
* Cyclins: Cyclin D, E, A, B
* transient expression, unstable
* activate CDKs
* Cyclin dependent kinase inhibitors
* inhibit CDKs
32
What effect do tumors have on cyclins cdks and cdk inhibitors
* tumors upregulate CDK and cyclins
* downregulate CDK inhibitors
33
what is an example of a cdk inhibitor/what is its function?
p16 (red light)
it inhibits **CDK4 and Cyclin D (green light)** so cells that are damaged don't replicate (enter G1)
34
WHat is the point of cell cycle check points and what happens when the genes that regulate these check points are mutated?
* 2 major checkpoints to ensure that damaged cells don't replicate
* mutatiosn in genes regulating check points allow cells with damaged DNA to replicate. once they replicate the daughter cells carry these mutations
35
What is the 2 hit hypothesis? What is an example?
* two mutations in tumor supressor genes are required for cancer progression (oncogenesis)
* ex: Retinoblastoma: mutations in 2 Rb genes are required to result in retinoblastoma development
* children get it sooner bc of this
36
What is the function of the Rb gene? what happens when it is hypo or hyper phosphorylated?
it governs the G1-S checkpoint of the Cell cycle
* when Rb is **hyper**phosphorylated **E2F is released** and cell enters S phase (transcription active)
* when Rb is **hypo**phosphorylated **E2F is** **sequestered** and the cell stays in G1 (no transcription)
37
what effect do growth factors have on Rb?
they phosphorylate Rb which releases E2F and the cell enters into the S phase (transcription)
38
all cancer shows dysregulated _______ checkpoint
G1-S checkpoint
39
What molecules are involved in the G1-S checkpoint
* p16-stop
* _Cyclin D1-go_
* _CDK4-go_
* CDK6
* Rb- phosphorylated=go, hypophosphorylated=stop
40
What state is Rb in during cancer
hyperphosphorylated-go!!!!
41
what is the function of p53
* senses cellular stress
* anoxia (tumors work under low oxygen and p53 can sense that)
* DNA damage
* Oncoprotein activity
* Directs cells to
* repair (GADD45)
* senescence (G1 arrest)
* apoptosis (BAX)
42
What are the mediators of p53, and what are thee functions?
p21-G1 arrest
GADD45- DNA repair
BAX-apoptosis
43
What family senses DNA damage and activates p53. How does it do this?
DNA damage is sensed by the ATM/ATR family. this activates p53 via release of MDM2
44
Most uman cancers have bialleic loss of\_\_\_\_\_\_
p53 (tumor supressor gene!)
45
What is the effect of MDM2 on p53? and what is required for a p53 response?
MDM2 inhibits TP53 when bound
MDM2 inactivation is required for TP53 response (ie tumor suression)
46
What is Li-Fraumeni Syndorme
* inheritance of a mutated p53 allele
* 25X risk of deeloping cancer by 50 yo
* younger age more cancers
* wide variety:
* sarcomas
* carcinomas: breast, brain, adrenal
* leukemias
47
WHat is HPV?
* DNA virus
* multiple gentically distinct subtypes with range of malignant potential
* LOW RISK: HPV-6 and 11 (warts)
* HIGH RISK: HPV 16, 18, 31, 33 (cancer)
48
WHat are the transforming effects HPV E6
* activate TERT: increase telomerase expression
* inhibit p53
these both lead to immortalization/increased cell proliferation and genomic instability (cancer)
49
* What are the transforming effects of E7?
* **inhibit p21** (which normally would put you into sensecence.) if it is inhibited then you have **increased CDK4/cyclin D** and those would inhibit RB-E2F meaning **E2F is free** (Rb hyperphosphorylated) and cell cycle continues
* **inhibit Rb-E2F** combo menaing RB is hyper so E2F is free and cell cycle continues
\*\*cancer
50
WHat happens when cancer mutates Rb and p53?
Rb: bypass checkpoints, unregulated growth
p53: increased rate of mutations (bc DNA not sensed)
51
What is APC and what occurs when it is mutated
* APC is a **tumor supressor gene** that mediates the destruction and down-regulation of B-catenin
* When APC is mutated with 2 hits
* B-catenin accumulation
* WNT activation (in absence of WNT)
* Upregulation: Cyclin D1, MYC, SLUG
* Reduced E-cadherin: loss of contact inhibition (lobar breast cancer)
52
What cancer commonly occurs as a result of an APC mutation
Familial adenomatous polyposis (FAP)
* a lot of polyps carpet the colon of adolescents, young adults
* invariable potential for malignant transformation to prophylactic colectomy
53
What are malignant gliomas? WHich grades are the most severe?
* molecularly heterogenous group of primary brain tumors arising from glial cells
* classified by integrating morphology and molecular alterations
* WHO grades: I, II, III, IV
* grades II to IV: diffusely invasice, surgical resection not possible, invariable progression
* tx: surgery, radiation therapy, and/or chemo
54
WHat drugs are used to treat malignant gliomas and what is the differnece betwee the two
Temozolomide (newly diagnosed)
Bevicuzimab (recurrent)
55
What are common mutations in Gliomas?
IDH1 or IDH2: isocitrate dehydrogenase
all repoted mutations are missense that lead to hypermethylation in the genome which turns off tumor supression genes
56
what is the typical function of IDH1?
transforms Isocitrate to aKG
this allows for resistance to apoptosis and protection to oxidative stress
57
WHat is the function of Bcl2 and how does it relate to folicular lymphoma?
* Bcl2 stops Bax/Bak from activating the intrinsic mitochondrial apoptotic pathway (Bcl2 stop apoptosis)
* follicular lymphoma=overexpression of Bcl2
* overexpression of Bcl2=no apoptosis=accumulation of lymphocytes in a folicle=follicular lymphoma
58
What needs to occur for a tumor to have limitless replicative potential?
1. no p53 (no tumor supression)
2. restoration of telomerase (no shortening of telomeres)
59
Tumors greater than 1mm require \_\_\_\_\_\_\_\_
vascularization
\*some drugs block angiogenesis to starev tumors
60
How are immune checkpoint inhibitors involved in cancer treatment
* checkpoint inhibiotrs put T cell into sensence
* drugs inhibit checkpoint inhibitor so that T cells are not in senescence aka are active and fight tumors
* PD-1 binds PDL1 (on tumor) =sensecence.
* drug: blocks PD1 so T cell is active (Nivolumab)
61
Inflammation by what viruses is associated with cancer and how do they lead to cancer?
Hepatitis B and C viruses
* 70-85% of hepatocellular carcinoma is due to HBV and HCV
* Inflammation:
* chronic hepatocellular injury
* stimulation of hepatocellular proliferation
* reactive oxygen species damage DNA
62
What are two possible acquired causes of genetic mutations?
1. underlying genetics (germline/inherited)
2. Environmental Exposure (somatic/acquired)
63
What 3 things are associated (caus) with DNA damage? inherited defects in DNA repair are associated wth wht?
chemicals, radiation, sunlight,
increased risk of cancer
64
What is lynch syndrome
a hereditary nonpolyposis colon cancer syndrome
* caused by mutations in Mismatch repair genes (MMR)
* these genes are supposed to catch mutations in DNA
* when they are mutated you can't catch DNA mutations so you get an accumulation of them which leads to cancer
*
65
What causes Xeroderma Pigmentosa
* risk of cancer on sun-exposed skin
* defective repair of UV damage to pyrimidines
* Defective nucleotide excision repair (NER) system
* multiple genes contribute to disease
66
What 4 diseases occur when you can;t repair DNA by homologous recombination
1. Fanconi anemia ( multigenic)
2. Bloom syndrome (BLM gene)
3. Ataxia-Telangiectasia (ATM gene)
4. Hypersensitive to DNA- damaging agents
67
BRCA1 and BRC2 genes mtations are associated with what?
* 50% of hereditary breast cancer but are rarely mutated in sporadic breast cancer
* theses genes function to repair DNA double stranded breaks by homologous recombination. mutation=not able to do their job and you get damage=cancer
68
what are 2 mechanisms by which microbes cause cancer
1. Viral genomic integration
1. overexpression of viral proteins that affect host cell growth
2. disrution of proto-oncogene= oncogene =cancer
2. Stimulation of host inflammatory response with subsequent regeneration
1. Hepatitis B,C
2. Helicobacter pylori
3. Schistosoma hematobium
69
What is Human T Cell Lymphotrophic Virus-1
* RNA virus that targets CD4 Tcells
* it activates TAX gene which activates cytokine genes in host T cells.
* T cell release cytokines-stimulates macrophages to release additional mitogens (actiavte T cells)
* **this establishes paracrine loops leading to proliferation**
70
What are the 2 way sthat Ebstein Barr Virus can lead to cancer?
* LMP1 oncoprotein
* stimulates proliferation via JAK2/STAT pathway
* inhibits apoptosis via BCL2 activation
* EBNA oncoprotein
* stimulates cyclin D1 and src
* EBV cancer is associated with immunocompromised pts.
71
What is H. pylori? What does it cause? and how does it cause it? And how do you treat it?
* bacteria that causes tumor growth
* gastric adenocarcinoma
* MALTomas
* Host inflammatory response leads to carcinogenesis
* inflammation causes: regernation, metaplasia, dysplasia, carcinoma
* treated with eradication of bacteria (reversible!!!!!!)
72
What are the 2 types of chemical carcinogens? What do these 2 things have in common?
* Direct-acting carcinognes: don;t require processing ie alkylatin agents
* Indirect acting carcinogens
* often metabolized by P450s
* must be actiavted
\*\*\*both direct and indirect acting carcinogens have the same target-nucleic acid\*\*\*
73
What polymorphic genes may contribute to carcinogenesis?
P450s 1A1-not a mutation just a variant that leads to increased risk of cancer
Glutathione S transferase- detoxifies polycyclin aromatic hydrocarbons, commonly deleted/mutated
74
What are the 2 classifications of carcinogenic compounds?
* initiator-chemicals that cause **permanent** DNA mutations
* direct and indirect
* permanent damage
* promoter- nontumorigenic chemical that enhances the proliferation of mutate cells; effect is reversible
\*\*\*\*without the presence of a promotor the initiator likely won't cause cancer
75
What is among the most potent chemical carcinogens? where is it found and what cancers is it associated with?
polycyclic aromatic hydrocarbons
found in coal, oil, iron, tobacco and are implicated in lung CA, bladder CA, laryngeal, oral cavity CA
76
WHat are the 2 kinds of radiation?
1. Ionizing radiation
* X-rays, y rays
* exposures from radiologic exams, occupational exposure, nuclear accidents, atomic bombs
* lesions from Hiroshima and Nagasaki
* leukemia
* breast, colon, thyroid, and lung cancer
* Lessons from Chernobyl
* throid cancer in children
2. UV light
* UVA, UVB, UVC
* formation of pyrimidine dimers
* nucleotide excision pathway
* xeroderma pigmentosa
* may also cause mutaions in protooncogenes
* skin cancer
* basal cell carcinoma (BCC)
* Squamous cell carcinoma (SCC)
Melanoma
