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Pathology 1 Block 2 > Neoplasia 3: Molecular Basis > Flashcards

Neoplasia 3: Molecular Basis Flashcards

1
Q

what are the 8 steps that lead to the essential alteration that lead to malignant transformation?

A
  1. cell begins making its own growth signals
  2. cell becomes insensitive to growth inhibition signals
  3. cellular metabolism altered
  4. apoptosis is evaded
  5. limitless replication
  6. sustained angiogenesis
  7. ability to invade (metastasize)
  8. immunity evasion
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2
Q

what is the Warberg effect?

A

cancer cells keep a high glucose uptake even when in too much presense of O2

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3
Q

What does it mean that cells produce their own growth signals?

A

it means that cells have proto-oncogenes that get modified into oncogenes in order to make oncoproteins which allows the production of growth factors

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4
Q

what do proto-oncogenes do?

A

Synthesis of growth factors, growth factor receptors, signal transducers, transcription factors

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5
Q

a mutation of a proto-oncogene will affect what?

A
  1. Growth factors
  2. Growth factor receptors
  3. Signal transducing proteins
  4. Transcription factors
  5. Cyclins & cyclin dependent kinases
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6
Q

give an example of a growth factor?

and a growth factor receptor?

A

PDGF

PDGFR

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7
Q

give an example of a proto-oncogene?

A

SIS

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8
Q

what is an example of a mutation that may cause tumor growth factor receptor activation?

A

point mutations

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9
Q

a point mutation in RET (protooncogene) can be seen in what diseases?

A

MEN (Multiple Endocrine Neoplasia) type 2A, 2B adn familial medullary carcinoma of the thyroid

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10
Q

a point mutation in c-KIT can be seen in what disease?

A

GIST (gastroinestinal stromal tumor)

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11
Q

a point mutation in FLT3 gene can be seen in what disease?

A

myeloid leukemia

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12
Q

a point mutation in RAS can be seen in what disease?

A

pancreatic adenocarcinoma

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13
Q

through what 3 characteristics do we identify MEN 1?

A

1) Primary hyperparathyroidism
2) Endocrine tumors of the pancreas
3) pituitary prolactinoma

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14
Q

MEN 2 is subclassified into what 3 syndromes?

A

1) MEN-2A
2) MEN-2B
3) familial medullary thyroid cancer

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15
Q

what is MEN 2A? (other name)

what symptoms will you see?

A

sipple syndrome

you will have: pheochromocytoma, medullary carcinoma of the thyroid, and parathyroid hyperplasia

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16
Q

what type of mutation occurs in MEN 2A?

A

germline gain-of-functoin

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17
Q

a point mutation in ALK gene can be seen in what disease?

A

lymphomas

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18
Q

in what disease do we see overexpression a gene?

A

ERBB1 - lung adenocarcinoma

ERBB2 - in breast cancer

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19
Q

what disease is this?

A

GIST

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20
Q

what is this?

A

GIST

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21
Q

what is the immunohistochemistry used for GIST?

A

c-kit (looks brown)

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22
Q

point mutation of what gene familly is the most common type of abnormality involving proto-oncogenes in human tumors?

A

ras gene

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23
Q

what genes make up the RAS family?

A

HRAS

KRAS

NRAS

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24
Q

in what cancers is the RAS point mutation the highest (90%)?

A

pancreatic adenocarcinoma

cholangiocarcinoma

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25
Q

in what cancers is the RAS point mutation 50% higher?

A

colon

endometrial

thyroid cancer

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26
Q

RAS stimulates what 2 receptor tyrosine kinase?

A

MAPK

IP3/AKT

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27
Q

what is this?

A

adenocarcinoma of colon

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28
Q

what is this?

A

adenocarcinoma of colon

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29
Q

how do you describe adenocarcinoma of colon?

A

ulceroproliferative lesion

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30
Q

BRAF is part of what gene family?

A

RAF

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31
Q

mutations in BRAF are seen in what cancer?

A

hairy cell leukemia and melanoma

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32
Q

JAK/STAT point mutation occurs where?

JAK/STAT activation thru’ point mutation seen in what disorders? give example of these disorders?

A

occurs in JAK 2

myeloproliferative disorders:

  • polycythemia
  • 1ry myelofibrosis
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33
Q

JAK/STAT point mutation is what type of alteration on tyrosine kinase?

A

non-receptor tyrosine kinase

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34
Q

in what diseases do we see alterations in non-receptor tyrosine kinase?

A

Chronic Myeloid Leukemia (CLL)

Acute Lymphoblastic Leukemia (ALL)

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35
Q

how do we get oncogenic BCR-ABL tyrosine kinase?

What is bad with BCR-ABL oncogene?

A

when C-ABL gets translocated from Ch. 9 to BCR region of Ch. 22

this chimeric gene is always active causing increase activity of ABL tyrosine kinase

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36
Q

what inhibits BCR-ABL tyrosine kinase?

A

imatinib mesylate

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37
Q

transcription factors include which products of proto-oncogenes?

A

MYC, MYB, JUN, FOS, and REL

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38
Q

what transcription factor is most commonly involved in human tumors?

A

myc

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39
Q

what is the genetic basis of burkitt lymphoma?

A

translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels

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40
Q

what is the translocation partner for MYC in burkitts lymphoma?

A

IgH locus t(8; 14)

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41
Q

what is this?

A

burkitts lymphoma

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42
Q

where do we see point mutation in N-MYC?

A

in neuroblastoma

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43
Q

what is the 3rd most common pediatric malignancy?

A

neuroblastoma

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44
Q

where does neuroblastoma originate?

where else can it arise from?

A

in the adrenal glands, neck, pelvis, brain

sympathetic ganglion

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45
Q

what is a good prognostic indicator of neuroblastoma?

A

absense of N-MYC amplification

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46
Q

What is the histology for neuroblastoma?

A

(embryonal) undifferentiated appearance = small round blue cell tumor

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47
Q

what hormones are produced in a neuroblastoma?

A

catecholamines

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48
Q

what is this?

A

neuroblastoma of the kidney

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49
Q

what are CDK’s? (cyclin dependant kinases)

A

control the cell cycle and move it forward by phosphorylating cyclin complexes

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50
Q

what are CDK inhibitors?

A

they stop the cell cycle

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51
Q

what stimulates CDK’s?

A

cyclins

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52
Q

what type of mutation will cause cyclin D1 to cause cancer?

This happens in what cancers?

A

gain of function

Mantle Cell Lymphoma

Breast carcinoma

Esophageal carcinoma

53
Q

what type of mutation in CDK inhibitors will lead to cancer?

give 2 example where this is seen

A

loss of function

germline mutation in p16:CDKN2A = melanomas

somatic mutation of p16 = 95% of pancreatic adenocarcinoma

54
Q

what do tumor suppressors do?

A

stop cell cycle and lead to failure of growth inhibition

55
Q

what are 3 examples of tumor suppressor genes?

A

RB VHL

p53 WT1

APC NF1

CDKN2A NF2

PTEN

56
Q

what happens if you have a oncogene but have a working tumor suppressor gene?

A

cells become quiescent

57
Q

how many of retinoblastomas occur spontaneously?

A

60%

58
Q

how many of retinoblastomas occur inherited?

A

40%

59
Q

what is knudson’s two hit mechanism for retinoblastoma?

A

both normal alleles of RB locus must be inactivated

60
Q

where do we find RB locus?

A

13q14

61
Q

what disease is this?

what is this symptom?

A

RB

leukocoria (cat eye reflex)

62
Q

what is knudson’s hypothesis mechanism in familial cases of retinoblastoma?

A

child is born with 1 defective gene (first hit is in germline)

later: 2nd copy of RB gene lost through somatic mutation

63
Q

what is knudson’s hypothesis mechanism in sporadic cases of retinoblastoma?

A

child born with 2 normal RB genes

both copies lost through somatic mutations

64
Q

familial cases of RB are more prone to what other malignancy?

A

osteosarcoma

65
Q

what is this?

A

retinoblastoma

66
Q

what is this?

A

retinoblastoma

67
Q

familial retinoblastoma is an example of a mutation occuring where?

A

germline

68
Q

sporadic retinoblastoma is an example of a mutation occuring where?

A

somatically

69
Q

what are 4 examples of somatic retinoblastoma?

A
  1. glioblastoma
  2. small cell carcinoma of lung
  3. breast cancer
  4. bladder cancer
70
Q

what is this?

how aggresive is it?

what may it cause?

A

astrocytoma = glioblastoma

very aggresive

may cause hemorrhage

71
Q

what is p53?

A

is in charge of:

  • regulating cell cycle progression
  • dna repair
  • apoptosis
72
Q

what is the most frequent mutated gene in human cancer?

A

TP53

73
Q

when tp53 is mutated, it is usually a gain or loss of function?

A

loss of function

74
Q

what is an example of a disease caused by a germline mutation of p53?

A

Li Fraumeni

75
Q

li fraumeni will cause what malignancies?

A

breast cancer

brain tumor

carcinoma of adrenal cortex

76
Q

tp53 has mutations more common occuring in somatic or germline?

A

somatic is more common

77
Q

what are the 3 interlocking mechanisms of p53 tumor suppressor gene?

A
  1. Activation of temporary arrest
  2. induction of permanent cell arrest
  3. triggering apoptosis
78
Q

what are the major roles of APC gene?

what is the main function of APC gene?

A
  • controlling cell fate, adhesion, cell polarity during embryonic development
  • hold β-catenin activity in check
79
Q

APC gene uses what signaling pathway?

A

WNT

80
Q

what do you get if you have a germline loss-of-function mutation in the APC ?

A

Familial adenomatous polyposis

81
Q

what is FAP (familial adenomatous polyposis)?

A
  • thousands of adenomatous polyps develop in the colon during their teens or early twenties
  • 1 or more of these polyps undergoes malignancy causing colon cancer
82
Q

non-familial colorectal carcinomas and sporadic adenomas also show acquired defects involving how many genes?

A

both APC genes

83
Q

what is this?

A

familial adenomatous polyposis

84
Q

what is the characteristic feature in carcinomas?

A

mutation causing e-cadhering loss and increase in ß-catenin

85
Q

how do cells that lose APC gene behave?

what is an example of a germline mutation that loses the APC gene?

what is an example of a somatic mutation that loses the APC gene?

A

like they are being continously stimulated by WNT

familial adenomatous polyposis

hepatoblastomas, hepatocellular carcinomas

86
Q

what causes FAP?

how are 75% of cases of FAP acquired?

how many polyps are needed in order to diagnose?

at what age is FAP diagnosed?

A

mutation of APC gene

inherited

100

30-50

87
Q

CDKN2A encodes for 2 proteins

A

1) p16/INK4a
2) p14/ARF

88
Q

what is p16/INK4?

what does it do?

A
  • cyclin dependant kinase inhibitor
  • blocks CDK4/cyclin D-mediated phosphorylation of RB
  • It reinforces RB checkpoint
89
Q

with what disease is CDKN2A mutation of the germline associated?

with what disease is CDKN2A sporadic mutation associated?

A

Familial Melanoma

bladder cancers, head and neck cancers, cholangiocarcinomas, and ALL

90
Q

what is the TGF-ß pathway

TGF-ß inhibits what?

how does it control it? what happens after?

how do the cellular signals differ when normal and when in cancer?

A

cell proliferation

by binding to TGF-ß receptro 1 and 2

activates SMAD proteins for cellular signals

normal = signal for anti-proliferative

cancer = no anti-proliferative effect through loss of function

91
Q

what diseases can be found or caused by a mutation of type 2 TGF-ß receptor?

A

colon cancer

stomach cancer

edometrial cancer

92
Q

mutational inactivation of SMAD4 is common in what cancer?

A

pancreatic cancer

93
Q

in what disease is PTEN mutated?

PTEN mutation causes what?

PTEN increases what types of cancer?

A

Cowden syndrome

frequent benign growths (skin appendage tumors)

breast, endometrial, thyroid

94
Q

what is this picture?

A

endometrial carcinoma due to PTEN mutation

95
Q

endometrial cancers are divided into what 2 categories?

Which category is the most common?

what condition predisposes to each category?

what gene mutation predisposes to endometrial cancer?

A

type 1 and 2

type 1

type 1 = endometrial hyperplasia

type 2 = endometrial atrophy

type 1 = PTEN

type 2 = TP53

96
Q

what protein defect is found in neurofibromatosis 1?

what is the funciton of this protein?

what patient with neurofibromatosis 1 develops benign neurofibromas?

what are the clinical features of neurofibromatosis 1?

A

neurofibrin 1

downregulation of the RAS signal transduction pathway (tumor suppresor)

those with 1 inherited mutant allele

symptoms: cafe-au-lait, lisch nodules (hamartomas in iris), neurofibroma

97
Q

what disease is this?

what is this?

A

neurofibromatosis

neurofibroma

98
Q

what disease is this?

what is this?

A

neurofibromatosis

lisch nodules

99
Q

what disease is this?

what is this?

A

neurofibromatosis

cafe au lait spots

100
Q

how do you get neurofibromatsis 2?

what is the classical presentation?

what happens if you have a sporadic mutation on both alleles?

A

germline mutation of neurofibrin 2

symptoms: benign bilateral schwannomas of the acoustic nerve (in skull)
- you see deafness and paralyzed

you will see sporadic meningiomas and ependymoma

101
Q

how does von Hippel-Lindau get mutated?

this can lead to what cancer?

when in life does this mutation occur or cancer occur?

what type of mutation will lead to the cancer?

what transcription factor gets degraded?

A

chromosome 3p

hereditary renal cancer, pheochromocytoma, hemangioblastoma of CNS

late in life

loss of function

HIF1alpha

102
Q

what is this?

what is it associated with?

A

renal carcinoma

mutation of von hippel-lindau

103
Q

what cell compose a pheochromocytoma?

what do these cells produce?

what is the rule of 10?

what are the clinical features of pheochromocytoma?

A

chromaffin cells

catecholamines

they are:

10% of sporadic are bilateral

10% are malignant

10% are not associated with hypertension

clinical features:

hypertension, sweating, palpitation, tremor

paroxysmal episodes: abrupt elevation of BP

104
Q

what will lab work show for pheochromocytoma?

A

elevated urinary excretion of free: vanillylmandelic acid and metanephrines

105
Q

what is this?

A

pheochromocytoma

106
Q

where is Wilms tumor suppressor gene located?

What does Wilm’s tumor cause?

in what age group do we see it?

WT1 protein is used for what?

A

Ch. 11p13

Wilm’s tumor

its pediatric

activates genes for renal and gonadal differentiation

107
Q

what is this?

A

wilms tumor

108
Q

what is BCL-2?

what is an example of a cancer that overexpresses BCL-2?

what is the translocation of this cancer?

A

anti-apoptotic factor

B cell lymphoma (follicular lymphoma)

t(14;18)

109
Q

true or false

all cancers have immortal cells?

telomerase activity is not seen in all tumor cells?

A

true

false

110
Q

what are the 3 factors that lead to immortality of cancer cells?

A
  1. evasion of senescense
  2. evasion of mitotic crisis
  3. capacity for self-renewal
111
Q

in cancer, there is neovascularization, what is this?

what is the purpose of neovascularization?

A

new vessels get formed from previously existing capillaries

It helps the tumor:

  • provides nutrients
  • new endothelial cells secrete growth factors
  • secrete VEGF, BFGF for angiogenesis
112
Q

mortality due to cancer is mostly due to what?

what are the 2 metastatic cascades of metastasis?

A

metastasis

1) invasion of ECM
2) vascular spreading, colonization

113
Q

what must happen for a tumor to invade the ECM?

A
  • basement membrane must be breached
  • crossing of interstitial connective tissue
  • invade circulaiton by breaking through basement membrane of blood vessel
114
Q

what are the general steps for a tumor to invade the ECM?

A
  1. tumor detaches from other tumor cells
  2. tumor cell arrives ECM
  3. ECM degraded
  4. tumor cell migrates
115
Q

what holds tumor cells together?

how do tumor cells break the basement membrane?

A

E-cadherins

by using MMP

116
Q

in circulation, how do we see tumor cells?

once in circulation, what do tumor cells use to adhere to selective sites?

prostatic adenocarcinoma favors what anatomical site to spread?

bronchogenic carcinoma favors what anatomic location to spread?

neuroblastoma favors what anatomic location to spread?

A

clumped

CD44 expressed on T cells

bone (mostly vertebral)

adrenals and brain

liver and bones

117
Q

what is this an example of?

A

vascular metastasis (tumor emboli)

118
Q

how do tumors evade host defense?

what patients have increased risk for developing cancer?

A

using cell-mediated mechanisms (tumor antigens get presented on cell surface using MHC 1 and get recognized by CD 8+)

immunosuppresed

119
Q

genomic instability

What are 3 mechanisms in the DNA repair system that can cause cancer?

A

1) mismatch repair
2) nucleotide excision repair
3) recombination repair

120
Q

what cancer can occur with mismatch DNA repair system?

what are the symptoms seen with this cancer?

mutation in what genes will lead to this cancer?

how do mismatch repair errors lead to mutations predisposing to cancer?

In what region do we find most mismatch mutations?

A

HNPCC

symptoms: lesion in proximal colon, no pre-existing colon

MSH2 or MLH1

they cause accumulations of many mutations

in microsatellite regions

121
Q

what disease is this?

A

FAP

because there are multiple polyps

122
Q

what is this?

A

HNPCC

because there is ulcero-proliferative growth (not polyp)

123
Q

what disease is an example of mutated nucleotide excision repair genes?

mutated nucleotide excision repair genes are involved in what type of cancers?

what is the mechanism by which this mutated genes cause the skin cancer?

A

xeroderma pigmentosum

skin cancers

(squamous cell carcinomas, basal cell carcinomas)

UV light causes cross-linking of pyrimidine residues

124
Q

what disorders are associated with recombination repair mutation?

what characterizes these disorders?

A

ataxia-telangiectasia, bloom syndrome, fanconi anemia

hypersensitivity to DNA damaging agents: ionizing radiation, DNA crosslinking agents

125
Q

what is the gene mutated in ataxia-telangiectasia?

what is the mechanism?

A

ATM gene

ATM gene recognizes DNA double-strand breaks caused by ionizing radiation

126
Q

what is this?

A

breast cancer (carcinoma of breast)

127
Q

what is this?

A

breast cancer (carcinoma of breast)

note: infiltrating malignant cells

128
Q

mutation of what genes are associated with breast carcinoma (cancer) and ovarian cancer?

which gene is related to what cancer? (of the 2 in previous question)

what is the normal function of these genes?

A

BRCA-1, BRCA-2

BRCA-1 = breast/ovarian cancer women

prostate cancer = men

BRCA-2 = breast cancer in men/women

ovarian/prostatic/pancreatic/bile duct cancer

transcription regulation & cell cycle control

129
Q

true of false

BRCA 1/2 are related to sporadic cases of breast cancer?

BRCA-1 is in what Chromosome?

BRCA-2 is in what Chromosome?

A

no, only to familial cancer

Ch. 17

Ch. 13

Pathology 1 Block 2 (8 decks)

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