T27 - Carcinogenesis I Flashcards by Bhargav Arimilli

What is the currently accepted basis of tumor progression?

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

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

proto-oncogenes (promote growth)

tumor suppressor genes (inhibit growth)

apoptosis regulators

DNA damage regulators

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

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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What are oncogenes?

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

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Differentiate between proto-oncogenes and oncogenes. (2)

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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What are oncoproteins?

protein product of oncogenes

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How do oncoproteins differ from their wild-type counterparts?

oncoproteins have mutations that specifically overexpress their activity

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

oncoprotein activity dominates

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

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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Growth factor receptors can promote tumorigenesis in what two ways?

mutation within protein leads to hyperactivity of receptors

regulatory mutation or DNA amplification increases expression of receptor

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

epidermal growth factor (EGF) receptor family:

ERBB1, the EGF receptor

HER2/NEU, a related receptor

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Describe ERBB1, the EGF receptor. (2)

overexpressed in ~90% of epithelial head/neck tumors

overexpressed in ~50% of glioblastomas

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Where is HER2/NEU commonly overexpressed?

HER2/NEU overexpressed in ~30% of breast cancers

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

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

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

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

trastuzamab/Herceptin

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What is RAS? (2)

the most commonly mutated proto-oncogene in human tumors

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

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

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

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

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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Explain how the most common RAS mutation affects its activity.

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

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What is ABL?

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

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Describe how ABL is altered in CML patients.

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

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

unregulated tyrosine kinase activity

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

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How is CML treated?

using Imatinib/Gleevec

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How do antigrowth signals prevent cellular proliferation? (2)

direct division-capable cells into G₀ (quiescence) direct division-capble cells to enter post-mitotic and differentiated state

What is retinoblastoma?

childhood malignancy of retinal epithelium

How is predisposition for tumorigenesis of retinoblastoma inherited?

autosomal dominant

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

_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

What is the cellular function of the RB gene?

regulates mitosis by controlling G1 → S transition

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

G1 → S transition

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

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

What is p53? (3)

tumor suppressor protein one of the most commonly mutated genes in cancer "guardian of the genome:

Through what three mechanisms does p53 fight off neoplastic transformation?

temporary cell cycle arrest = quiescence permanent cell cycle arrest = senescence apoptosis

Which protein inhibits p53 activity?

MDM2

What is Li-Fraumeni syndrome?

result of _inheriting_ a mutant p53 allele

What is adenomatous polyposis coli?

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

Is adenomatous polyposis coli lethal?

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

What is the cause of adenomatous polyposis coli?

loss of tumor suppressor APC gene

What is the inheritance pattern of Li-Fraumeni syndrome?

autosomal dominant (two-hit hypothesis)

What protein in adenomatous polyposis coli is unregulated?

beta-catenin

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

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

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

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

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

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

How does the APC disease progress? (2)

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

What is the relationship between BCL2 and apoptosis?

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

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

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

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

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

How do neoplastic cells avoid mitotic crisis and become "immortal?"

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

How is sustained angiogenesis developed in tumors?

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

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

breaking of cell-cell contacts degradation of ECM attachment of migrating cells to new ECM components migration of tumor cells to distant site

What is the rate limiting step in tumor metastasis?

migration of tumor cells to distant site

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

first capillary bed they encounter

What is organ tropism?

some tumors show a preference for metastasizing to a particular organ

What are the three common karyotypic changes observed in tumors?

balanced translocations deletions gene amplifications

Balanced translocations are especially common in which types of tumors?

hematopoietic neoplasms soft tissue sarcomas

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

hereditary nonpolyposis colon cancer syndrome xeroderma pigmentosum BRCA1/BRCA2-related breast cancer

What are three common pediatric malignant tumors?

neuroblastoma Wilms tumor rhabdomyosarcoma

Neoblastoma: age of onset

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

Neoblastoma: prognosis

better prognosis if \<1 y/o

How can neoblastoma be clinically identified?

serum or urine levels of catecholamines or dopamine metabolites

What is notable about neuroblastoma?

most common solid tumor in children, outside of CNS

What are the biological markers of neuroblastoma? (2)

NMYC amplification tumor ploidy (worse when diploid)

Wilms tumor: age of onset

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

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

most common childhood renal tumor 4th most common pediatric tumor overall

How does a Wilms tumor present?

asymptomatic abdominal mass accidentally discovered by a parent

Describe the appearance of the Wilms tumor. (2)

large, spherical, sharply circumscribed from kidney soft, pale

The Wilms tumor most commonly metastasizes to

the lungs

Wilms tumor: prognosis

excellent (\>80%)

Rhabdomyosarcoma: age of onset

5-14 years old

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

head and neck GU extremities

What are the three types of rhabdomyosarcomas?

embryonal botryoid alveolar

Describe the features of embryonal rhabdomyosarcoma.

pleomorphic hyperchromatic

Describe the features of botyroid rhabdomyosarcoma.

grape-like masses projecting into lumen of bladder or vagina

Describe the features of alveolar rhabdomyosarcoma. (3)

translocation involving FKHR and PAX3/7 sheets of malignant cells separated by thin, fibrous septa worst prognosis

Give two examples of tumors resulting from balanced translocations.

alveolar rhabdomyosarcoma Ewing sarcoma

Give an example of a tumor that shows organ tropism.

prostate adenocarcinoma

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.

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

overexpression of proto-oncogenes (in the case of BCL2 and follicular lymphoma) oncogenic fusion proteins (in the case of BCR-ABL and CML)

Neuroblastomas arise in what tissue?

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