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Flashcards in Molecular oncogenesis Deck (50):

Name a couple ways of how malignant cells thrive or grow

Evade apoptosis
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Tissue invasion and metastasis
Limitless replicative potential
Sustained angiogenesis


What is the molecular basis of cancer?

Non-lethal genetic alterations -- key to carcinogenesis


What are some of the regulatory gene targets for cancer?

Tumor suppressor genes
Antiapoptosis genes
Apoptosis genes
DNA repair genes


Describe protooncogenes.

Normal regulatory genes, involved in regulating normal cell growth, expression is under tight control


Describe oncogenes

Cancer genes, involved in autonomous, unregulated cell proliferation in cancer cells, expression is constitutive, only one mutant allele required (gain of function).

Protooncogene + alteration = oncogene


How do tumors learn to respond to growth factors?

They acquire the ability to produce GF to which they are responsive. They may develop GF receptors.


What growth factor does the SIS gene produce and what does it lead to?

beta-PDGF --> overexpression and drives proliferation of astrocytomas/osteosarcomas


How do growth factors normally responds and how does that differ from when they become cancer growth factors?

Normally they are on when a growth factor binds and off when it does not. Cancer leads to abnormal constitutive activation. (ERB B2 gene -- HER2/Neu and c-KIT gene)


What does amplification of the ERB B2 (Her-2-Neu) growth factor mean?

Poor prognostic sign in breast cancer and predicts unresponsiveness to estrogen therapy. Patients will be receptive to Trastuzumab (Herceptin).


What drug targets the c-KIT mutation in GISTs and what does it do?

Imatinib mesylate (Gleevec) -- tyrosine kinase inhibitor


What are the functions of signal transducing proteins?

They normally receive signals from receptor-ligand complexes and transiently transduce signal into organelles.


Signal transducing protein that contains point mutations in 15-20% of all tumors. GTP binding proteins with reduced GTPase activity. Potential chemotherapy target.

RAS oncogene family
K-RAS in pancreas and colon CA
H-RAS in bladder and kidney CA


Signal transducing protein that has transient tyrosine kinase activity. Cancer results from a translocation between 9th & 22nd Philedelphia chromosome.

c-ABL gene

Translocation creates a bcr-abl fusion product. Present in chronic myelogenous leukemia and acute lymphoblastic leukemia. Detected by cytogenetics and PCR. Results in a loss of regulatory control = constitutively active.


What is the role of transcription factors?

They bind to DNA and control transcription of genes (activation or inhibition).


Transcription factor that activates a wide range of genes. Usually under tight regulation -- transient increase in expression following a signal to replicate and then rapid return.

MYC oncogene

C-MYC: mutated form that leads to continued expression
N-MYC: mutated form that leads to amplification


Increased expression in Burkitt Lymphoma
Results from t(8;14) --> becomes under regulation of IgG heavy chain and loses tight regulation

c-MYC gene


Amplification in neuroblastoma with poor prognosis

n-MYC gene


Name two main cell cycle regulators.

Cyclins: transient expression, activate CDKs
CDKs (cyclin-dependent kinases): constitutively expressed, phosphorylate target proteins


What is the function of cyclin D?

Activates CDK4 and that complex phosphorylates Rb protein


How does cyclin D1 become oncogenic?

t(11;14) --> cyclin D1-IgH fusion, over expression of cyclin D1. Detected by cytogenetics and immunohistochemistry. Present in mantle cell lymphoma, minor pop in plasma cell myeloma and hairy cell leukemias.


What is the function of tumor suppressor genes??

Normal genes that are responsible for controlling cell proliferation.


How do mutations need to occur in tumor suppressor genes for oncogenesis?

Mutations in both alleles are required = loss of function


Explain the two-hit hypothesis and related it to Retinoblastoma.

Retinoblastoma is the model. Both alleles must be inactivated. Two different ways this can happen Familial and Sporadic.


What happens when there are mutations in the RB gene?

RB encodes a tumor suppressor protein, which is a cell cycle regulator. Mutations cause a failure of E2F regulation, allowing for uncontrolled E2F activation and unregulated cell growth --> retinoblastoma


Gene involved in destruction and down-regulation of B-catenin.

APC gene (tumor supressor)


What happens when there are mutations in APC?

Mutations lead to loss of regulation -- B-catenin accumulation which complexes with TCF (transcription factor) and stimulates the transcription of other growth factors and lead to unregulated cell growth!!


What do mutations in APC predispose individuals to?

Familial adenomatous polyposis (FAP) -- individuals get >100 mucosal polyps that carpet the colon of adolescents, young adults. Potential for malignant transformation of polyps --> have prophylactic colectomy


What is the normal function of p53?

Cell cycle arrest, initiate apoptosis following DNA damage


Explain Li-Fraumeni Syndrome.

Inheritance of a mutated p53 allele -- 25x risk of developing cancer by 50 yo compared to general population


Pro-apoptotic protein



Anti-apoptotic protein



Which anti-apoptotic gene is over expressed in many lymphomas? How does this happen?

t(14;18) --> IgH-bcl-2 fusion of follicular lymphoma leads to over expression of BCL-2 and tumor progression due to inhibition of normal apoptosis, rather than uncontrolled cell proliferation


How does mutation have to occur to DNA repair genes?

Usually requires loss of both alleles


Direct acting carcinogens

Highly reactive, electron deficient compounds that react with electron-rich sites (DNA, RNA, protein)


Indirecte acting carcinogens

Metabolized by cytochrome P-450 systems


Metabolizes polycyclic aromatic hydrocarbons, 10% of caucasions have highly inducible form which leads to increased carcinogens, risk of CA



detoxifies polycyclic aromatic hydrocarbons, 50% of caucasians have deletions which leads to increased carcinogens, risk of CA



Chemical that causes permanent DNA mutations



Nontumorigenic chemical that enhances that proliferation of mutated cells; effect is reversible


Example: hormones


What is the carcinogen mainly responsible for lunch cancer from tobacco smoke? Are they initiators or promoters?

Polycyclic aromatic hydrocarbons


Radiation with UV light leads to what kind of mutations?

Formation of pyrimidine dimers -- nucleotide excision pathway, Xeroderma pigmentosa (predisposition)


How can microbes cause oncogenesis?

Viral genome integration --> over expression of viral proteins which affect host cell growth, disruption of protooncogene
Stimulation of host inflammatory response with subsequent regeneration


Explain how EBV may lead to oncogenesis.

Seen first in oropharynx, then infects B cells in tissue of oropharynx through CD21 receptor --> 2 things happen:
1. Healthy -- B cells infected and then T cells capture or limit the response (self-limited infection)
2. Immunosuppressed -- don't have T cells to tightly regulate B cell proliferation so they have B cell growth, proliferation and tumor growth (Burkitt lymphoma)


Name some EBV associated malignancies.

Burkitt lympoma
Post-transplant lymphoproliferative B-cell disorders
B-cell lymphomas in immunosuppressed
NK/T cell lymphoma, nasal type
Hodgkin lymphoma
Nasopharyngeal carcinoma


What are the two genes that get messed up regulation in HPV?

E6 and E7 --> overexpression


What are the low risk and high risk types of HPV?

Low risk: 6, 11
High risk: 16, 18, 31, 33


How can Hep B and Hep C lead to oncogenesis?

Chronic liver injury leads to regeneration
HBx protein in Hep B activates growth genes, inhibits p53


How can cirrhosis lead to hepatocellular carcinoma?

Regenerative nodular hyperlast (normal response) but increased risk of genetic abnormalities with continued proliferation


What types of cancer can Helicobacter pylori cause?

Gastric adenocarcinoma


What is it that leads to carcinogenesis in Helicobacter pylori infections?

The host inflammatory response