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Tissues > T27 - Carcinogenesis I > Flashcards

T27 - Carcinogenesis I Flashcards

1
Q

What is the currently accepted basis of tumor progression?

A

stepwise accumulation of mutations — in other words, a mutation in a single gene isn’t sufficient to cause cancer

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2
Q

What are the four types of regulatory genes associated with cancer?

A

proto-oncogenes (promote growth)

tumor suppressor genes (inhibit growth)

apoptosis regulators

DNA damage regulators

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3
Q

What are the six hallmark perturbations of physiology that lead to cancer?

A

changes in:

self-sufficiency (growth)

insensitivity to inhibition (growth)

evasion of apoptosis (survival)

limitless replicative potential (survival)

development of sustained angiogenesis (survival)

ability to invade and metastasize (spread)

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4
Q

What are oncogenes?

A

genes that promote autonomous cell growth in cancer upon genetic mutation or overproduction

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5
Q

Differentiate between proto-oncogenes and oncogenes. (2)

A

proto-oncogenes are the wild-type versions of oncogenes

proto-oncogenes have neoplastic potential because they can be mutated which leads to constitutive activity

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6
Q

What are oncoproteins?

A

protein product of oncogenes

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7
Q

How do oncoproteins differ from their wild-type counterparts?

A

oncoproteins have mutations that specifically overexpress their activity

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8
Q

Which is more dominant — oncoprotein activity, or protooncoprotein activity?

A

oncoprotein activity dominates

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9
Q

Write out the pathway of normal cell proliferation regulation. (5)

A

binding of growth factor activates cell membrane receptors → activated cell membrane receptors activate signal transduction proteins → transmission of signal from cytosol to nucleus → activate DNA transcription factors → entry into cell cycle

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10
Q

Growth factor receptors can promote tumorigenesis in what two ways?

A

mutation within protein leads to hyperactivity of receptors

regulatory mutation or DNA amplification increases expression of receptor

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11
Q

Which family of receptors provides the best example of overexpression leading to oncogenesis? Give two examples of receptors within this family.

A

epidermal growth factor (EGF) receptor family:

ERBB1, the EGF receptor

HER2/NEU, a related receptor

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12
Q

Describe ERBB1, the EGF receptor. (2)

A

overexpressed in ~90% of epithelial head/neck tumors

overexpressed in ~50% of glioblastomas

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13
Q

Where is HER2/NEU commonly overexpressed?

A

HER2/NEU overexpressed in ~30% of breast cancers

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14
Q

Describe the relationship between HER2/NEU and tumor growth. (2)

A

HER2/NEU-positive tumors are very sensitive to growth factors, leading to high rate of growth

high HER2/NEU expression means poor prognosis

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15
Q

Explain how HER2/NEU-positive tumors are clinically treated.

A

humanized anti-HER2/NEU antibodies bind to EC domain of the HER2/NEU receptors and block activation/activity

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16
Q

What are the drug/trade names for the anti-HER2/NEU antibodies?

A

trastuzamab/Herceptin

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17
Q

What is RAS? (2)

A

the most commonly mutated proto-oncogene in human tumors

member of small G-protein superfamily that binds GDP/GTP

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18
Q

What is the most commonly mutated proto-oncogene in human tumors?

A

RAS (nearly 30% of all human tumors involve mutated RAS)

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19
Q

Describe the interaction between RAS and GDP/GTP. (4)

A

RAS proteins inactive when bound to GDP

upon growth factor stimulation, RAS exchanges GDP for GTP and becomes active

active RAS signals to downstream cellular proliferation pathways

RAS then self-inhibits activity via hydrolysis of GTP to GDP

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20
Q

Explain how the most common RAS mutation affects its activity.

A

most common RAS mutation eliminates intrinsic RAS GTP hydrolysis activity, meaning it’s always activated

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21
Q

What is ABL?

A

non-receptor-associated tyrosine kinase proto-oncogene that, when normal, is subject to regulatory control

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22
Q

Describe how ABL is altered in CML patients.

A

in CML patients, gene for ABL is fused with BCR gene due to chromosomal translocation (Philadelphia chromosome, t9:22)

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23
Q

What are the cellular effects of having a fused BCR-ABL gene in CML patients? (2)

A

unregulated tyrosine kinase activity

abnormal localization within the cell (can’t go to the nucleus like ABL is supposed to)

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24
Q

How is CML treated?

A

using Imatinib/Gleevec

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25
Q

How do antigrowth signals prevent cellular proliferation? (2)

A

direct division-capable cells into G0 (quiescence)

direct division-capble cells to enter post-mitotic and differentiated state

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26
Q

What is retinoblastoma?

A

childhood malignancy of retinal epithelium

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27
Q

How is predisposition for tumorigenesis of retinoblastoma inherited?

A

autosomal dominant

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28
Q

Explain why retinoblastoma is inherited in an autosomal dominant manner, even though the gene itself acts recessively. (3)

A

two-hit hypothesis:

if child inherits one defective RB and one normal RB, no tumorigenesis

but, if spontaneous somatic mutation/epigenetic silencing knocks out the normal gene, then tumorigenesis can occur

in other words, only one defective copy needs to be inherited to initiate tumorigenesis

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29
Q

What is the cellular function of the RB gene?

A

regulates mitosis by controlling G1 → S transition

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30
Q

Which transition in the cell cycle is considered to be MOST important in the context of neoplasia?

A

G1 → S transition

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31
Q

Describe how the retinoblastoma protein normally functions as a cell cycle checkpoint enforcer. (6)

A

RB protein active/hypophosphorylated in early G1 → RB protein binds to E2F transcription factors → in growth conditions, RB protein hyperphosphorylated by CDKs and inactivated → E2F freed from inhibition → production of cyclin E → mitosis

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32
Q

What is p53? (3)

A

tumor suppressor protein

one of the most commonly mutated genes in cancer

“guardian of the genome:

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33
Q

Through what three mechanisms does p53 fight off neoplastic transformation?

A

temporary cell cycle arrest = quiescence

permanent cell cycle arrest = senescence

apoptosis

34
Q

Which protein inhibits p53 activity?

A

MDM2

35
Q

What is Li-Fraumeni syndrome?

A

result of inheriting a mutant p53 allele

36
Q

What is adenomatous polyposis coli?

A

rare disease in which patients develop hundreds-thousands of adenomatous polyps in colon, small intestine, and stomach

37
Q

Is adenomatous polyposis coli lethal?

A

if left untreated, polyps will be transformed into invasive carcinoma and will be deadly

38
Q

What is the cause of adenomatous polyposis coli?

A

loss of tumor suppressor APC gene

39
Q

What is the inheritance pattern of Li-Fraumeni syndrome?

A

autosomal dominant (two-hit hypothesis)

40
Q

What protein in adenomatous polyposis coli is unregulated?

A

beta-catenin

41
Q

Describe the interaction between APC and beta-catenin in a wild-type patient.

A

APC binds to β-catenin and causes its degradation, preventing cyclin-D1 and MYC genes from being activated

42
Q

In a wild-type patient, what would release APC from beta-catenin?

A

Wnt signaling degrades APC and allows beta-catenin to translocate to the nucleus and stimulate expression of cyclin-D1 and MYC

43
Q

Describe the interaction of APC and beta-catenin in patients with APC.

A

both copies of APC mutated, so APC-dependent degradation of beta-catenin doesn’t occur, meaning it is constantly stimulating expression of cyclin-D1 and MYC

44
Q

How does the APC disease progress? (2)

A

inheritance of one mutant allele, but additioanl mutations leads to multifocal polyp development

somatic loss of both APC alleles (i.e. loss of heterozygosity) is seen in 70% of cases → earliest stage of malignancy

45
Q

What is the relationship between BCL2 and apoptosis?

A

BCL2 inhibits apoptosis by preventing permeabilization/breakdown of mitochondrial outer membrane, a step necessary to initiate apoptosis

46
Q

What is the genetic cause of B-cell follicular lymphoma?

A

chromosomal translocation that involves the region of chromosome 18 that codes for BCL2

47
Q

Explain how the chromosomal translocation in B-cell follicular lymphoma patients affects BCL2 activity.

A

BCL2 gene fused to immunoglobulin heavy-chain gene, which is highly expressed, so BCL2 becomes highly expressed → increased inhibition of apoptosis

48
Q

How do neoplastic cells avoid mitotic crisis and become “immortal?”

A

re-express or overexpress telomerase to prevent telomere shortening, which would normally trigger cell cycle arrest

49
Q

How is sustained angiogenesis developed in tumors?

A

cancer or surrounding cell uses factors such as vascular endothelial growth factor (VEGF) or HIF1-alpha for neovascularization

50
Q

What are the four necessary steps for a tumor to metastasize?

A

breaking of cell-cell contacts

degradation of ECM

attachment of migrating cells to new ECM components

migration of tumor cells to distant site

51
Q

What is the rate limiting step in tumor metastasis?

A

migration of tumor cells to distant site

52
Q

For metastatic cells that enter the blood supply, what is often the first metastatic site?

A

first capillary bed they encounter

53
Q

What is organ tropism?

A

some tumors show a preference for metastasizing to a particular organ

54
Q

What are the three common karyotypic changes observed in tumors?

A

balanced translocations

deletions

gene amplifications

55
Q

Balanced translocations are especially common in which types of tumors?

A

hematopoietic neoplasms

soft tissue sarcomas

56
Q

Give three examples of diseases that originate from mutations in DNA repair systems.

A

hereditary nonpolyposis colon cancer syndrome

xeroderma pigmentosum

BRCA1/BRCA2-related breast cancer

57
Q
A
58
Q

What are three common pediatric malignant tumors?

A

neuroblastoma

Wilms tumor

rhabdomyosarcoma

59
Q

Neoblastoma: age of onset

A

0-9 years old, with <2 years old most common

60
Q

Neoblastoma: prognosis

A

better prognosis if <1 y/o

61
Q

How can neoblastoma be clinically identified?

A

serum or urine levels of catecholamines or dopamine metabolites

62
Q

What is notable about neuroblastoma?

A

most common solid tumor in children, outside of CNS

63
Q

What are the biological markers of neuroblastoma? (2)

A

NMYC amplification

tumor ploidy (worse when diploid)

64
Q

Wilms tumor: age of onset

A

0-4 years old, with 2-4 y/o most common

65
Q

What is the significance of the Wilms tumor? (2)

A

most common childhood renal tumor

4th most common pediatric tumor overall

66
Q

How does a Wilms tumor present?

A

asymptomatic abdominal mass accidentally discovered by a parent

67
Q

Describe the appearance of the Wilms tumor. (2)

A

large, spherical, sharply circumscribed from kidney

soft, pale

68
Q

The Wilms tumor most commonly metastasizes to

A

the lungs

69
Q

Wilms tumor: prognosis

A

excellent (>80%)

70
Q

Rhabdomyosarcoma: age of onset

A

5-14 years old

71
Q

Which sites are most commonly affected by rhabdomyosarcoma? (3)

A

head and neck

GU

extremities

72
Q

What are the three types of rhabdomyosarcomas?

A

embryonal

botryoid

alveolar

73
Q

Describe the features of embryonal rhabdomyosarcoma.

A

pleomorphic

hyperchromatic

74
Q

Describe the features of botyroid rhabdomyosarcoma.

A

grape-like masses projecting into lumen of bladder or vagina

75
Q

Describe the features of alveolar rhabdomyosarcoma. (3)

A

translocation involving FKHR and PAX3/7

sheets of malignant cells separated by thin, fibrous septa

worst prognosis

76
Q

Give two examples of tumors resulting from balanced translocations.

A

alveolar rhabdomyosarcoma

Ewing sarcoma

77
Q

Give an example of a tumor that shows organ tropism.

A

prostate adenocarcinoma

78
Q

Write out the steps of multistep carcinogenesis, using the adenoma-carcinoma sequence of colorectal carcinoma as an example. List the steps in molecular changes as well as morphological changes.

A
79
Q

In the context of translocations, tumorigenesis is typically caused in what two ways?

A

overexpression of proto-oncogenes (in the case of BCL2 and follicular lymphoma)

oncogenic fusion proteins (in the case of BCR-ABL and CML)

80
Q

Neuroblastomas arise in what tissue?

A

sympathetic nervous system → then 50% presentation in abdominal, 50% presentation in adrenal

Tissues (23 decks)

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