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FPP Block 1 > Tumor Oncogenesis > Flashcards

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

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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

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3
Q

Describe the basic molecular pathology of cancer

A

genetic variants in DNA and RNA lead to diagnosis prognosis and treatment

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4
Q

What are oncognenes?

A
  • one mutant gene (domniant)
  • constitutive activation (fuel)
  • growth factors and receptors
  • signaling molecules
  • transcription factors
  • “Driver mutation”
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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

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6
Q

Genetic lesions=____________

A

Variants!

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7
Q

What are small genetic lesions and what do they cause?

A
  • single nucleuotide variant
  • insertion/deletion (indel)
  • simple to detect
    *
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8
Q

What are large genetic lesions and what do they lead to

A
  • copy number variants, structural variants
  • complex to detect
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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**

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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
    *
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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
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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
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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
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14
Q

WHat are passenger mutations?

A
  • acquired mutation that does not contribute to cancer phenotype
  • may synergize with driver mutations
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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
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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

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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
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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)

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19
Q

how do we treat a KIT mutation?

A

CKIT tyrosine kinase inhibitor

drug name: Imatinib (Gleevec)

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20
Q

Mutations don’t need to be directly in DNA they can be in ________

A

signal transducing proteins

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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
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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

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23
Q

What is BRAF? WHat kind of cancers result when mutated?

A

serine/threonin protein kinase

hairy cell leukemias

melanomas

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24
Q

what drugs are used to treat cancer caused by a BRAF mutation?

A

Vemurafenib

Dabrafenib

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25
Q

WHat is a philadelphia chromosome fusion oncoprotein? What causes this?

A
  • 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)
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26
Q

what cancers are associated with a philadelphia chromosome fusion oncogene? WHat is the treatment

A
  • 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”
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27
Q

what is oncogene addiction

A

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

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28
Q

What influence do oncogenes have on transcription factors? what are some examples?

A
  • 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
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29
Q

What is Myc? What results from activation of MYC gene

A

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
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30
Q

WHat type of cancer is associated with Myc mutations?

A

Burkitt Lymphoma

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31
Q

What are the cell cycle regulators?

A
  • 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
Q

What effect do tumors have on cyclins cdks and cdk inhibitors

A
  • tumors upregulate CDK and cyclins
  • downregulate CDK inhibitors
33
Q

what is an example of a cdk inhibitor/what is its function?

A

p16 (red light)

it inhibits CDK4 and Cyclin D (green light) so cells that are damaged don’t replicate (enter G1)

34
Q

WHat is the point of cell cycle check points and what happens when the genes that regulate these check points are mutated?

A
  • 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
Q

What is the 2 hit hypothesis? What is an example?

A
  • 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
Q

What is the function of the Rb gene? what happens when it is hypo or hyper phosphorylated?

A

it governs the G1-S checkpoint of the Cell cycle

  • when Rb is hyperphosphorylated E2F is released and cell enters S phase (transcription active)
  • when Rb is hypophosphorylated E2F is sequestered and the cell stays in G1 (no transcription)
37
Q

what effect do growth factors have on Rb?

A

they phosphorylate Rb which releases E2F and the cell enters into the S phase (transcription)

38
Q

all cancer shows dysregulated _______ checkpoint

A

G1-S checkpoint

39
Q

What molecules are involved in the G1-S checkpoint

A
  • p16-stop
  • Cyclin D1-go
  • CDK4-go
  • CDK6
  • Rb- phosphorylated=go, hypophosphorylated=stop
40
Q

What state is Rb in during cancer

A

hyperphosphorylated-go!!!!

41
Q

what is the function of p53

A
  • 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
Q

What are the mediators of p53, and what are thee functions?

A

p21-G1 arrest

GADD45- DNA repair

BAX-apoptosis

43
Q

What family senses DNA damage and activates p53. How does it do this?

A

DNA damage is sensed by the ATM/ATR family. this activates p53 via release of MDM2

44
Q

Most uman cancers have bialleic loss of______

A

p53 (tumor supressor gene!)

45
Q

What is the effect of MDM2 on p53? and what is required for a p53 response?

A

MDM2 inhibits TP53 when bound

MDM2 inactivation is required for TP53 response (ie tumor suression)

46
Q

What is Li-Fraumeni Syndorme

A
  • 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
Q

WHat is HPV?

A
  • 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
Q

WHat are the transforming effects HPV E6

A
  • activate TERT: increase telomerase expression
  • inhibit p53

these both lead to immortalization/increased cell proliferation and genomic instability (cancer)

49
Q
  • What are the transforming effects of E7?
A
  • 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
Q

WHat happens when cancer mutates Rb and p53?

A

Rb: bypass checkpoints, unregulated growth

p53: increased rate of mutations (bc DNA not sensed)

51
Q

What is APC and what occurs when it is mutated

A
  • 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
Q

What cancer commonly occurs as a result of an APC mutation

A

Familial adenomatous polyposis (FAP)

  • a lot of polyps carpet the colon of adolescents, young adults
  • invariable potential for malignant transformation to prophylactic colectomy
53
Q

What are malignant gliomas? WHich grades are the most severe?

A
  • 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
Q

WHat drugs are used to treat malignant gliomas and what is the differnece betwee the two

A

Temozolomide (newly diagnosed)

Bevicuzimab (recurrent)

55
Q

What are common mutations in Gliomas?

A

IDH1 or IDH2: isocitrate dehydrogenase

all repoted mutations are missense that lead to hypermethylation in the genome which turns off tumor supression genes

56
Q

what is the typical function of IDH1?

A

transforms Isocitrate to aKG

this allows for resistance to apoptosis and protection to oxidative stress

57
Q

WHat is the function of Bcl2 and how does it relate to folicular lymphoma?

A
  • 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
Q

What needs to occur for a tumor to have limitless replicative potential?

A
  1. no p53 (no tumor supression)
  2. restoration of telomerase (no shortening of telomeres)
59
Q

Tumors greater than 1mm require ________

A

vascularization

*some drugs block angiogenesis to starev tumors

60
Q

How are immune checkpoint inhibitors involved in cancer treatment

A
  • 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
Q

Inflammation by what viruses is associated with cancer and how do they lead to cancer?

A

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
Q

What are two possible acquired causes of genetic mutations?

A
  1. underlying genetics (germline/inherited)
  2. Environmental Exposure (somatic/acquired)
63
Q

What 3 things are associated (caus) with DNA damage? inherited defects in DNA repair are associated wth wht?

A

chemicals, radiation, sunlight,

increased risk of cancer

64
Q

What is lynch syndrome

A

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
Q

What causes Xeroderma Pigmentosa

A
  • 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
Q

What 4 diseases occur when you can;t repair DNA by homologous recombination

A
  1. Fanconi anemia ( multigenic)
  2. Bloom syndrome (BLM gene)
  3. Ataxia-Telangiectasia (ATM gene)
  4. Hypersensitive to DNA- damaging agents
67
Q

BRCA1 and BRC2 genes mtations are associated with what?

A
  • 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
Q

what are 2 mechanisms by which microbes cause cancer

A
  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
Q

What is Human T Cell Lymphotrophic Virus-1

A
  • 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
Q

What are the 2 way sthat Ebstein Barr Virus can lead to cancer?

A
  • 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
Q

What is H. pylori? What does it cause? and how does it cause it? And how do you treat it?

A
  • 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
Q

What are the 2 types of chemical carcinogens? What do these 2 things have in common?

A
  • 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
Q

What polymorphic genes may contribute to carcinogenesis?

A

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
Q

What are the 2 classifications of carcinogenic compounds?

A
  • 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
Q

What is among the most potent chemical carcinogens? where is it found and what cancers is it associated with?

A

polycyclic aromatic hydrocarbons

found in coal, oil, iron, tobacco and are implicated in lung CA, bladder CA, laryngeal, oral cavity CA

76
Q

WHat are the 2 kinds of radiation?

A
  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

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