T27 - Carcinogenesis I Flashcards
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
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
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)
What are oncogenes?
genes that promote autonomous cell growth in cancer upon genetic mutation or overproduction
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
What are oncoproteins?
protein product of oncogenes
How do oncoproteins differ from their wild-type counterparts?
oncoproteins have mutations that specifically overexpress their activity
Which is more dominant — oncoprotein activity, or protooncoprotein activity?
oncoprotein activity dominates
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
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
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
Describe ERBB1, the EGF receptor. (2)
overexpressed in ~90% of epithelial head/neck tumors
overexpressed in ~50% of glioblastomas
Where is HER2/NEU commonly overexpressed?
HER2/NEU overexpressed in ~30% of breast cancers
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
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
What are the drug/trade names for the anti-HER2/NEU antibodies?
trastuzamab/Herceptin
What is RAS? (2)
the most commonly mutated proto-oncogene in human tumors
member of small G-protein superfamily that binds GDP/GTP
What is the most commonly mutated proto-oncogene in human tumors?
RAS (nearly 30% of all human tumors involve mutated RAS)
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
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
What is ABL?
non-receptor-associated tyrosine kinase proto-oncogene that, when normal, is subject to regulatory control
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)
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)
How is CML treated?
using Imatinib/Gleevec
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
