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MyDermatology-Bolognia > Ch. 107-Principles of tumor biology > Flashcards

Ch. 107-Principles of tumor biology Flashcards

1
Q

What are the 4 stages of cell cycle

A

G1
S-dna synthesis
G2
M-mitosis

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2
Q

Which major protein families regulate the cell cycle?

A

Cyclins
Cyclin dependent kinases (CDK): work to phosphorylate/activate cyclins

Cyclin dependent kinase inhibitors (CKIs): binds to the complexes and halts DNA progression to allow for corrections in DNA

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3
Q

What regulates CKIs?

A

P53

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4
Q

What transcription factor allows g1- to progress S phase?

What protein allows the TF to progress

A

E2-F

Rb if phosphorylated

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5
Q

What happens if Rb is under-phosphorylated?

A

Rb binds to E2-F (transcriptions factor) and cell cycle progression halts, thus tumor supressor gene

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6
Q

What is the main gene that controls Rb phosphorylation?

A

CDK2NA

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7
Q

What does CDK2NA act as? what are its gene products and their actions?

A

Tumor supressor

P16-CKI that blocks Rb phosphorylation
P14 ARF-binds to MDM2, resulting in an increase in p53

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8
Q

What gene is mutated in familial melanoma

A

CDKN2A

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9
Q

What is the main regulator G1 checkpoint? How/through which mechanisms?

A

P53

In DNA damage, P53 activate-> activates multiple CKIs including p15, p16, p18 and p19. These bind to Rb and ensure underphosporylated. Rb therefore binds to E2-F (transcription factor) and prevents G1—> S progression.

Additionally via CDKN2A, p14 ARF binds MDM2, resulting in an increase in p53 through interference with the p53–MDM2 feedback loop

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10
Q

What is a driver vs. passenger mutation?

A

driver mutations confer a selective growth advantage to the cancer cells

passenger mutations that have no effect on tumorigenesis

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11
Q

What is an oncogene?

A

Oncogene: Genes that gain oncogenic potential via mutation (gain of function or increase in gene function)

Proto-oncogene: gene involved in normal cell growth. mutates to become oncogene

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12
Q

What is a tumor suppressors gene?

A

tumor suppressor genes act by inhibiting proteins that control cell cycle progression

Cancer occurs when develop inactivation/loss of function

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13
Q

Which gene mutations (oncogene and tumor suppressor gene) active in dominant and recessive fashions? What does this mean?

A

Oncogene- dominant: only need one allele mutated

Tumor supressor gene - recessive: mutation in one allele has no effect

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14
Q

What are some examples of oncogenes?

A

PDGFB, HRAS, SRC, RAF1, MYC, FOC

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15
Q

What are some supressor genes?

A

RB1
TP53
BCL2
CDKN2A

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16
Q

What is loss of heterozygosity?

A

LOH: when the 2nd normal/wild-type allele, is lost as well, and you have change from heterozygous to homozygous recessive

Multiple ways this can occur:
-point deletion
-epigenetic silencing
-point mutations
-insertions
etc.

Can inherit the “first hit” in certain familial cancer syndromes

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17
Q

Is Rb tumor supressor gene or oncogene? MOA?

A

Tumor supressor:

  • underphosphorylated Rb blocks proliferation of cell cycle and acts as breaks via blocking transcription factor E2F
  • Serine/threonine phosphorylation of Rb results in activation of E2F transcription factor
  • Genes that control Rb phosphorylation are TUMOR SUPRESSOR GENES, and when mutated have loss of these genes that maintain underphosphorylation
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18
Q

What is special about TP53 genes in regards to dominant or recessive effects?

A

It is a tumor supressor gene but can act in dominant negative fashion
(tetramer protein that often joins both alleles gene products)

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19
Q

Apoptosis Vs. Necrosis

A

Necrosis is due to poor nutrient supply, leading to membrane disruption, cell lysis, no de novo protein synthesis

Apoptosis if programmed cell death and requires de novo protein synthesis, mediated by proteases termed “caspases” causing DNA fragmentation, degradation cytoskeleton and degradation of laming

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20
Q

What is the main anti-apoptotic protein?

A

BCL-2

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21
Q

What is a the main pro-apototic protein?

A

BAX

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22
Q

What can trigger apoptosis? 3 mechanisms

A

DNA damage (UV, chemical)
Death promoting agents: TNF
Withdrawl growth stimulatory signals (e.g. EGF, TGF alpha, PDGF)

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23
Q

How does P53 regulate BAX and BCL-2

A

P53 blocks BCL-2 (L=Life=no apoptosis)

P533 promotes BAX transcription thereby encouraging apoptosis

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24
Q

How is P53 involved in angiogenesis

A

P53 activates thrombospondin which inhibits angiogenesis

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25
Q

What are some ways we can lose P53 function?

A

Genomic alterations in TP53

Binding to viral proteins

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26
Q

What chromosome is TP53 on?

A

Chromosome 17

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27
Q

What is TP53 encode?

A

P53 nuclear phosphoprotein

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28
Q

What does P53 do?

A

Tumor supressor gene
4 functional domains:
- transcription, DNA binding, oligomerization, and auto-inhibition

Mostly exerts function at level of transcription

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29
Q

What are 6 genes that are regulated by P53 tetramer?

A

CDKN1A (cell cycle inhibition-activates)
GADD45A (cell cycle inhibition-activates)
BAX (apoptosis-activates)
Thrombospondin (inhibits angiogenesis-activates)
MDM2 (regulatory-inhibits–> MDM2 binds and inactivated P53 itself thus feedback loop)
BCL-2 (inhibits apoptosis- inhibits)

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30
Q

What does P53 do in response to DNA damage?

A

Rapid increases in P53, experts multiple effects including:

  • cell cycle arrest at G 1 in order to facilitate the repair of damaged DNA prior to cell division
  • apoptosis occurs thenas a response to irreversible damage of genomic DNA and prevents survival of cells with severe genetic alterations
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31
Q

What changes occur in response to DNA damage?

A
  1. P53 increases–> cellular and DNA proofreading, cell cycle arrest, apoptosis if needed.
  2. P21 increases which inhibits cyclin-dependent kinases, inhibits phosphorylation Rb, underphosphorylated RB binds to E2F and prevents progression of S cycle
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32
Q

Is PTCH1 a oncogene or tumor supressor

A

tumor supressor gene

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33
Q

What are the players involved in sonic hedgehog pathway

A

Sonic hedgehog ligand (SHH)
Patched (PTCH1) akan sonic hedgehog receptor
Smoothened (SMO)
Gli (GLI)

34
Q

What are the genes involved in hedgehog pathway

A

Hedgehog:
sonic hedgehog (SHH)
indian hedgehog
desert hedgehog

PTCH1 and PTCH2

GLI1, GLI2, GLI3

35
Q

PTCH1 gene: what is its product?

A

PATCHED or “sonic hedgehog receptor”

  • transmembrane protein
  • ligand is sonic hedgehog
36
Q

What is normal function SHH pathway

A

early embryologic development, including formation of the neural tube, musculoskeletal system, hematopoietic cells, skin, and teeth

37
Q

Describe the sonic hedgehog pathway

A
  1. Unbound Patched (PTCH1) silences Smoothened (SMO) signalling. In this state GLI (transcription factor), is bound to SUFU and is not activated
  2. If Hedgehog (SHH) binds to Patched, Smoothened signalling transduction is activated via signalling through GLI to the nucleus (Sufu becomes unbound from GLI)
38
Q

What mutations can occur in hedgehog pathway? How do these mutations manifest clinically?

A
  1. Mutations in PTCH1/patched result in constitutive Smoothened activation and GLI transcription factor and downstream gene activation
    e. g. Gorlins and occasionally sporadic BCCs
  2. An activating mutation in SMO results in constitutive signaling to GLI and downstream target genes
    e. g. Sporadic BCCs
39
Q

What are some genes transcribed when the sonic hedgehog pathway is turned on?

A

GLI (itself)
PTCH1 (negative feedback loop)
BCL2

Others- 
MYCN (the DNA-binding protein)
B-catenin
FOX family proteins
cyclins
runt-related transcription factor 3 (nuclear effector of TGF-Beta family)
40
Q

What are other tumours are linked to dysfunctional SHH pathway?

A

Medulloblastoma
Ovarian and cardiac fibromas

*Seen in BCNS

41
Q

What mutation is seen in BCNS? what chromosome? What is its mode of inheritance?

A

PTCH1 mutation on chromosome 9q22-31.
Autosomal dominant

Born with 1 dysfunctional allele typically, thus at increased risk for LOH and also likely haploinsufficiency occurring? I think.

Most with BCNS and sporadic BCC have both alleles mutated.

42
Q

Can BCC develop anywhere on the body?

A

No. Only areas with pilosebaceous units. Commonly nose

43
Q

What are some theories why BCC do not metastasize?

A

BCCs are dependent on stroma produced by dermal fibroblasts.

44
Q

Why do BCCs tend to invade?

A

Increased expression of enzymes such as metalloproteinases and collagenases in BCC cells and surrounding stromal cells

45
Q

What mutations are found in BCCs and in what orders

A
  1. PTCH1 mutations, majority
  2. TP53 mutations, around 50%
  3. SMO in 20%

*GLI up regulation seems to be a key and driving factor in BCC development

46
Q

What type of UV exposure increases risk BCC the most? SCC?

A

High-dose intermittent for BCC, especially early in life suburns

Chronic long term/cumulative dose over lifetime for SCC

47
Q

Risk of mets in SCC?

A

5%

48
Q

High risk factors for mets in SCC?

A 
Location: Lips, ears, anogenital
Tumor depth: > 6mm risk is 14%
Tumor diameter: >2cm
Poorly differentiated
perineurial invasion >0.1mm
49
Q

What is the main gene mutated in SCC?

A

UV irradiation of normal skin induces mutations in TP53 gene in keratinocytes and facilitates clonal expansion of those cells.
Further mutations in TP53 can occur

50
Q

What are precursors to invasive SCC?

A 
Actinic keratoses (partial thickness epidermal dysplasia)
SCC in situ (full thickness) 
-Bowens
-Bowenoid
-erythroplasia queyrat
Invasive SCC
-well diferentiated
-poorly differentiated
Verrucous carcinoma
51
Q

What is one difference between BCC and SCC that may explain differences in ability to metastasize?

A

SCC not dependent on surrounding stroma for growth

52
Q

What are some other mutations in SCC?

A 
CDK2NA
ras oncogene-10-50%, some say 3-30%
c-Myc oncogene in up to 50% immunosuppressed
NOTCH1 and NOTCH2
KNSTRN
53
Q

Compared to BCC, what are the general changes to the genome in SCC?

A

more widespread genomic copy number variations with deletions and gains in several chromosomes.

54
Q

What is the mechanism of keratinocyte carcinoma related to BRAF inhibitor treatment?

A

RAS mutations/activation of the MAPK pathway

55
Q

What is the most common mutation in SCC in patients on BRAF inhibitors?

A

RAS mutations (>60%)

56
Q

Explain photocarcinogenesis chain of events

A

UV exposure
DNA damage (pyrimidine dimers)
Mutation (C–>T is signature UV mutation)
Skin cancer

57
Q

What are DNA photoproducts

A

DNA is a chromophore that when absorbs UVB/UVC, and somewhat UVA, undergoes changes to generate photoproducts

Specifically, DNA photoproducts are DIMERS–> formed by covalently binding two adjacent pyrimidines in the same polynucleotide chain

58
Q

What are the two pyridines

A

Thymine
Cytosine
(Uracil in RNA)
They are single rings

59
Q

What are the two major DNA photoproducts?

A

Cyclobutane pyrimidine dimers (most common)

6’4-photoproducts

60
Q

What is a cyclobutane pyrimidine dimer?

A

Two adjacent pyrimidines covalently bond to form a 4-membered cyclobutyl ring (dipyrmidine)

61
Q

What is the most common pyrimidine dimer?

A

(T–T) being the most common
C–T and T–C dimers
C–C dimers are the least common

62
Q

What is a 6,4-photoproduct

A

Non-cyclobutyl ring dipyrimidine photoproduct formed by:

-covalent linkage C-6 pyrimidine with the C4 of the adjacent pyrimidine at the 3’ end

63
Q

What is the most common 6-4 photoproducts

A

T–C (6–4) dimer is the most common dimer of this type

C–C and T–T dimers are also seen

64
Q

What are the signature mutations of UV mutagenesis?

A

C–>T and CC–>TT mutations

65
Q

How do pyrimidine dimers lead to mutation and cancer?

A

Pyrimidine dimers result in improper DNA pairing and cause C→T single base transition mutations at this site, or tandem CC–>TT (10% of the time)

These specific mutations are really only found in skin cancer which is why they are “UV signatures”

these occur in TP53 gene (often leading to SCC) and PTCH1/SMO genes in BCC, and CDK2NA and PTEN in some melanomas.

66
Q

What are some differences in P53 mutation between SCC vs. BCC/melanoma

A

P53 mutations ocyr EARLY in SCC, likely a driver mutation

- occur later in on in carcinogenesis of BCC/melanoma

67
Q

What are the mutated genes in nevus sebaceous? What conditions are you at an increased risk of?

A

HRAS or KRAS

-mildly increased risk BCC, increased risk trichoblastoma

68
Q

What mutations occur in keratoacanthomas?

A

upregulation of genes involved in cell death and apoptosis pathways-could explain regression spontaneously

Sporadic TP53, NOTCH1/2, PI3CA (but not + in regressing KAs)

69
Q

Gene mutated in Ferguson Smith?

A

TGFBR1

70
Q

What set of genes mutated in XP? XP variant?

A

XP: NER protein genes (nuclear excision repair)

XP variant: DNA polymerase eta (POLη)

71
Q

What is Li-Fraumeni syndrome? What gene is mutated?

A

TP53 is important Germline

familial cancer syndrome–> breast cancer, brain tumors, osteosarcoma, and leukemia

72
Q

What tumors are increased in BCNS?

A 
BCC
Cardiac fibromas
Ovarian fibromas
Ovarian cancer
Meningioma
medulloblastoma
73
Q

What is Bazex-dupre-Christol syndrome? What is the gene mutation/chromosome effected? Mode inheritance?

A

Genodermatosis of: follicular atrophoderma, congenital hypotrichosis, early onset BCCs

X-linked dominant (no male-male transmission)

Mutation likely on chromosome Xq24–q27

74
Q

What chromosome is TP53 on?

A

Chromosome 17

75
Q

What chromosome is PTCH1 on?

A

Chromsome 9

76
Q

What are the main proteins that promote cell division

A

cyclins

77
Q

What gene encodes p16

A

CDK2NA

78
Q

Where do vismodegib and sonidegib act?

A

Inhibits activated smoothened. Resistance to this medication occurs with mutations of smoothened

79
Q

What is the increase in risk of skin cancer for those with xeroderma pigmentosum?

A

100x

80
Q

What gene ismutated in familial melanoma

A

MyDermatology-Bolognia (31 decks)

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