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Pathology > Malignancy hallmarks - Robyns Chapter 7 > Flashcards

Malignancy hallmarks - Robyns Chapter 7 Flashcards

1
Q

What is MSI and how does it relate to dMMR

A

Microsatellite instability is a genetic result of deficient mismatch repair. Tandem repeats of nucleotides throughout the genome become variable in length as opposed to being very constant where mismatch repair is normal.

Ie, dMMR can be tested by:
-IHC testing for abnormal levels of key mmr proteins
-molecular testing to detect downstream MSI

Robyns pg 314

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2
Q

Define constitutive activation

A

Mutation leads for a pathway to be in an activated state without any need for its usual activating factor, and resistant to down regulating signals.

Pg 284

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3
Q

Define tumour suppressor gene

A

A gene which, when acting normally, provides growth inhibitory/ regulating signals which keep cell growth in check. Mutation causes a loss in function which then allows for growth signal pathways to proceed with less inhibition.

Pg 291

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4
Q

Define proto-oncogene

A

A gene, which when mutated results in a product which is constitutively activated and free of either need for growth factor activation or free from being inhibited. Ie, a gain of functional activity due to mutation.

Pg 284

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5
Q

What are the hallmarks of cancer

A

Evasion of immune system
Self sufficiency of growth signals
Invasion and Metastasis
Evading growth suppressors
Replicative immortality
Altered cellular metabolism
Evasion of apoptosis
Sustained angiogenesis

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6
Q

What type of protein is ALK

A

A receptor tyrosine kinase

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7
Q

What type of protein is HER2, what gene encodes it

A

A receptor tyrosine kinase, encoded by ERBB2

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8
Q

What type of protein is EGFR, and what gene encodes it?

A

A tyrosine kinase, encoded by ERBB1

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9
Q

What are the most common types of abnormality of the gene encoding EGFR

A

Point mutations resulting in constitutive activation

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10
Q

What is the most common type of abnormality of the gene encoding HER2?

A

Up regulation of gene causing receptor over expression

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11
Q

What is the most common abnormality of the gene encoding ALK

A

Gene rearrangement resulting in a constitutively activated form

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12
Q

What type of proteins are RAS proteins?

A

Membrane associated small g-proteins. Bind GTP/GDP (GTP in active form), tranducing growth pathway signals from the receptor tyrosine kinase to intracellular pathways

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13
Q

What are the most common type of mutation of RAS proteins and what is the resulting abnormality

A

Point mutations. Result in less function of GTPase activity of the RAS protein, so the RAS protein remains in its active state.

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14
Q

Why are RAS protein and receptor tyrosine kinase mutations almost mutually exclusive?

A

Because if RAS proteins are mutated resulting in constitutional activity there is no need for it to receive signalling from the tyrosine kinase inhibitor

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15
Q

What type of protein does the NF1 gene produce

A

A GTPase activating protein (GAP). These upregulate the intrinsic GTPase activity of RAS proteins up to 1000 fold. therefore mutation will result in increased activity of associated RAS proteins.

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16
Q

What are the complexes that progress cells through the cell cycle, and what activated them

A

Cyclin dependent kinases. Activated by cyclin proteins

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17
Q

What cascade are RAF (eg BRAF) proteins part of

A

The MAPK cascade (a downstream part of growth factor signalling pathways)

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18
Q

What cascade results in the transcription of the MYC gene, and what are the functions of the MYC protein

A

Part of the RAS-MAPK cascade.
MYC is a transcription factor that upregulates many genes;
Many effects of hallmarks of cancer
-D cyclins
-rRNA genes
-promoting Warburg effect
-upregulates expression of telemorase
-may promote stem cell-like properties

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19
Q

What are examples of epigenetic aberrations sometimes found in malignancy

A

DNA methylation
Histone acetylation

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20
Q

What is the function of p16

A

Cyclin dependent kinase inhibitor. Ie inhibits cell cycle progression. Binds to cyclin D/CDK4,6 (stops their phosphorylation of RB) and cyclin E/CDK2 to inhibit them

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21
Q

What is associated with p16 to form its functional unit

A

INK4a

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22
Q

What is the Warburg effect

A

Tumour cells changing their metabolic state, switching to aerobic glycolysis

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23
Q

What are the two major downstream signalling arms from RAS

A

-MAPK cascade
-PI3K/AKT

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24
Q

Why have drugs targeting RAS mutations been unsuccessful

A

Because they would have to restore the missing enzymatic activity of GTPase

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25
Q

What gene encodes e-cadherin , and what are the two major functions

A

CDH1
Transmembrane protein that contributes to cohesion of normal epithelial cells
Tumour suppressor

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26
Q

What cancers are associated with inherited heterozygous CDH1 mutation

A

E-cadherin gene
Lobular carcinoma of breast
Signet ring carcinoma of the stomach

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27
Q

What abnormalities of MYC occur in cancer

A

A multitude
-chromosomal translocation (eg burketts)
-upregulation of upstream signalling pathways
-RAS-MAPK pathway (many cancers)
-Notch signalling (many cancers)
-Wnt pathway (colon ca)
-hedgehog signalling (medulloblastoma)
-single nucleotide polymorphism in surrounding enhancing elements flanking the MYC gene (prostate, ovarian)

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28
Q

What are the four phases of the cell cycle

A

G1
S (synthesis)
G2
M (mitosis)

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29
Q

Which cancers have upregulation of the CDK4 gene?

A

Melanoma
Glioblastoma
Sarcomas

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30
Q

Abnormalities in which cyclin and CDK are most important in malignancy, and why

A

Cyclin D/CDK4 because the are the main ones controlling the G1/S checkpoint. If this checkpoint fails it is much more likely that a mutator phenotype can develop. Also key to dysregulated growth

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31
Q

What is the specific function of CyclinD/CDK4

A

Phosphorylation RB, releasing RBs breaks on transcription factor E2F, allowing G1/S cell cycle progression

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32
Q

What is E2F

A

A transcription factor that drives transition through the G1/S checkpoint

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33
Q

What protein complex inhibits MDM2

A

p14/ARF.
By inhibiting MDM2 it increases p53 levels

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34
Q

What malignancies are associated with somatic mutation/inactivation of p16

A

Glioblastoma (40-70%)
Oesophageal (50%)
Pancreatic (75%)
ALL (20-70%)
NSCLC (20%)

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35
Q

What tends to happen in cells with intact tumour suppressor pathways that develop a mutant oncogene

A

They enter cell cycle arrest or apoptosis

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36
Q

What cancers are associated with familial Rb mutation

A

Retinoblastoma (10000 times increased risk)
Osteosarcoma
Other soft tissue sarcomas

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37
Q

What is the inheritance pattern of familial Rb mutation

A

Autosomal dominant
-but cancer only develops when the normal allele also gets mutated in a retinoblast (or other cell leading to a sarcoma) leading to both Alleles being mutated

38
Q

Which cyclin/CDK complexes contribute to phosphorylation of Rb

A

CyclinD/CDK4
CyclinD/CDK6
CyclinE/CDK2

39
Q

What are the 4 key regulators of cell cycle progression, with one dysregulated in majority of cancers

A

CDK4
Cyclin D
Rb
p16/INK4a

40
Q

How do high risk HPV variants cause dysregulation of the cell cycle

A

They produce protein E7, which binds to hypophosphorylated Rb, preventing it binding to E2F. Thus it’s transcriptional function becomes uninhibited.
E7 also inhibits p21 and p27 which are CDK inhibitors

41
Q

Why is p16 raised in HPV associated cancers

A

Due to feedback loop. P16 levels rise in an attempt to prevent hyperphosphorylation of Rb. This is unsuccessful as Rb has been inactivated by E7 rather than hyperphosphorylation

42
Q

What is the most mutated gene in human cancers

A

TP53

43
Q

What are the functions of p53

A

Regulation of cell cycle progression
DNA repair
Promotion of cellular senescence
Apoptosis

44
Q

What syndrome results from TP53 mutation

A

Li Fraumeni syndrome.
25-fold greater risk than general population of malignancy. Can be of any type

45
Q

What proportion of sarcomas have upragulated MDM2

A

33%. Therefore used as a bio marker for sarcomas

46
Q

What is the effect of E6 protein produced by high risk HPV

A

Binds to p53 and promotes its degradation
Also upregulates telomerase, thus promoting immortality of cells

47
Q

How do DNA damage and hypoxia result in p53 upregulation

A

ATM and ATR sense these changes (both involved in DNA repair pathways)
Both phosphorylate MDM2 and p53, which releases p53 from MDM2 binding and breakdown

48
Q

How is p53 upregulated by “oncogenic stress” (upregulates cell cycle signalling)

A

P14/ARF levels rise (via incompletely understood mechanism)
This complex binds MDM2, releasing p53

49
Q

What gene encodes p14/ARF

A

CDKN2A
Ie the same gene that encodes p16/INK4a

50
Q

What is a pathway by which p53 promotes cell cycle arrest

A

Causes transcription of the CDKN1A gene. This produces p21 which inhibits CDK4/CyclinD (similar to p16)

51
Q

What are the broad functions of p53

A

Cell cycle arrest
Enhanced DNA repair
Apoptosis
Senescence
Enhanced catabolic metabolism rather than anabolic

52
Q

What genes does p53 direct transcription of to promote apoptosis

A

PUMA
BAX

53
Q

What is thought to cause p53 to promote a pro-apoptosis pathway

A

Sustained high levels of p53 due to ongoing cellular stress. Ie, it first promotes cell cycle arrest and DNA repair, then later apoptosis if that has failed

54
Q

Why do cancers with p53 mutations tend to have worse outcomes

A

-Due to mutator pho type they are likely to have a wide variety of genetically distinct sub clones that don’t all respond to the same therapy
-because they have a looks of apoptosis promotion they are less likely to respond to chemotherapy and radiation therapy

55
Q

What cancers is familial NF1 mutation associated with

A

Neuroblastoma
Juvenile myeloid leukaemia
Peripheral nerve sheath tumours
Neurofibromas

56
Q

What cancers is familial NF2 mutation associated with

A

Acoustic scwannoma
Meningioma

57
Q

What syndrome is APC associated with

A

Adenomatous polyposis coli

58
Q

What signalling pathway is APC part of, what is the role of normal APC

A

Part of the WNT signalling pathway. It normally binds to B-Catenin in the absence of activation of the WNT receptor and causes the breakdown of B-Catenin.

59
Q

What is the normal action of B-Catenin

A

It binds to a transcription factor in the nucleus, leading to transcription of genes that promote cell cycle progression such as MYC and cyclin D

60
Q

What is the normal interaction between B-catenin and E-cadherin

A

B-catenin binds to the cytoplasmic tail of e-cadherin and this regulates b-catenin, reducing its activity in promoting transcription of cell cycle genes. This normal interaction is to promote healing of wounds

61
Q

What is the the function of the TGF-B pathway

A

A potent inhibits pathway of proliferation by:
-upregulation of genes such as CDK inhibitors
-downregulation of proliferative genes such as MYC, CDKs, cyclins

62
Q

What is a key inhibitor of the PIK3/AKT pathway

A

PTEN

63
Q

What is the function if HIF1a

A

Levels increase in hypoxia conditions to promote increased expression of VEGF as thus promote angiogenesis
Also promotes change in cellular metabolism to aerobic glycolysis (Warburg effect)

64
Q

What is the key function of VHL

A

In the presence of oxygen it binds of HIF1a and promotes its breakdown. Thus reducing downstream effects promoting angiogenesis.
Also binds to other proteins promoting their breakdown

65
Q

What malignancies commonly have mutated VHL

A

Renal cell carcinomas

66
Q

What does the NF2 gene produce

A

Merlin, a tumour suppressor

67
Q

What is the normal role of PD-1

A

It is used by T and B cells of the immune system to recognise normal host cells (by recognising PD-L1) and avoid attacking these normal cells. Ie, prevent autoimmune disease

68
Q

What is an immune checkpoint inhibitor target on host immune cells other than PD-1

A

CTLA 4- Ipilimumab

69
Q

Describe the changes happening as part of the Warburg effect

A

Aerobic glycolysis. Cancer cells change to glycolysis metabolism even in the presence of normal oxygen. This promotes increased glucose uptake by cells and conversion of this to lactose (fermentation)

70
Q

What imaging modality makes use of the Warburg effect

A

FDG PET

71
Q

What is the normal type of metabolism of glucose in well oxygenated cells

A

Oxidative phosphorylation

72
Q

What is the advantage for a cancer cell in using aerobic glycolysis rather than oxidative phosphorylation

A

It produces metabolic intermediates the cell can use to synthesise cellular components

73
Q

Which cell signalling pathways promote aerobic glycolysis

A

PI3K/AKT
MYC

74
Q

In general, is autophagy enhanced or suppressed in malignant cells

A

Suppressed

75
Q

What metabolic process is IDH part of

A

The krebs cycle (used by quiescent cells to produce ATP

76
Q

What does IDH mutation do to its function

A

Changes its enzymatic activity, with production of abnormal metabolites (2-HG). One effect is to cause abnormal DNA methylation and expression.

77
Q

What are the two pathways that can induce apoptosis

A

Intrinsic
Extrinsic (mediated by TNF proteins)

78
Q

What pro and anti-apoptotic proteins act in balance on the mitochondria, what is the result of increased pro apoptotic signalling

A

Pro: BAX, BAK
Anti: BCL-2, BCL-XL (neutralised by proteins. Like PUMA)
If pro apoptotic signalling becomes dominant they cause the mitochondrial membrane to become for porous, releasing caspase C.

79
Q

What is the interaction between p53 and PUMA

A

p53 upregulates PUMA

80
Q

What translocation is involved in follicular lymphoma, and what is the key gene involved. Why does it result in a slow growing tumour

A

14:18 involving the BCL2 gene (an anti apoptotic gene)
It results in slow growing tumours because it results in less cellular death rather than increased cellular proliferation

81
Q

What anti apoptotic protein has inhibitor medications frequently used in lymphoma/leukaemia treatment

A

BCL2

82
Q

What cancers are associated with Cowden syndrome

A

PTEN mutation (inhibitor of PI3K/AKT pathway)
Breast, thyroid, endometrial carcinoma

83
Q

What are different examples of small round blue cell tumours

A

Ewing sarcoma
Neuroblastoma
Medulloblastoma
Small cell lung cancer
Merkel cell cancer
Small cell lymphoma
Mesothelioma
Wilms tumour

84
Q

What pathways does ALK activate

A

JAK and STAT pathways

85
Q

What is a key factor that induces normal tissue inflammation and growth of connective tissue in response to radiation

A

TGF-B

86
Q

What is the effect of TNF in response to radiation in normal tissues

A

Induces proliferation of fibroblasts, inflammatory cells, endothelial cells

87
Q

What syndrome is associated with familial CDH1 mutation, and what are the two main cancers associated with it

A

E cadherin gene
Familial diffuse gastric carcinoma syndrome

Lobular breast cancer
Signet ring carcinoma of the stomach

88
Q

What are microscopic features commonly associated with aggressive tumours. Ie, things to say when you don’t know

A

High mitotic rate
Necrosis
Pleomorphism/ cytological atypia
Infiltrating growth
Vascular invasion
PNI

89
Q

What is the most hereditary tumour, and what syndromes is it associated with

A

Pheochromocytoma

-MEN2 (RET)
-NF1
-SDH (more commonly associated with Mets)

90
Q

Which genes are associated with SDH deficient tumours, what is tested for

A

SDHA, SDHB (most common) SDHC, SDHD.

IHC for SDHB LOSS. This will occur for any of the mutations above, not just SDHB

91
Q

What tumours are associated with SDH mutation

A

Pheochromocytoma/paraganglioma
GIST
SDH deficient RCC

92
Q

What is the Carney triad

A

Tumours associated with non hereditary SDHC promoter hypermethylation

-paraganglioma
-GIST
-pulmonary chondroma

Pathology (16 decks)

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