Molecular oncogenesis Flashcards
What is the key molecular basis for cancer?
Non-lethal genetic alterations
Examples of genetic alterations (4)
- Point Mutations
- Balanced translocations
- Gene deletions
- Gene amplification/overexpression
What are methods for laboratory detection? (5)
- Conventional cytogenics
- Fluorescent-labeled DNA probes
- PCR
- Immunohistochemistry
- Nucleic acid sequencing
What are gene tarets for cancer and what kind of mutation leads to cancer for each? (5)
- Proto-oncogenes - Activations
- Tumor suppressor genes - Inactivation
- Antiapoptosis genes - Activation
- Apoptosis genes - Inactivation
- DNA repair genes - Inactivation
What is a proto-oncogene?
Genes involved in regulating normal cell growth
Normally expression is under tight controls
Functions usually are: GFs, GF Receptors, Signal transducer, TFs, Cell-cycle regulators
What is an oncogene?
Gene involved in autonomous, unregulated cell proliferation
Constitutive expression, no regulation
Mutant allele results in gain of function
Formed from the combination of a proto-oncogene and a genetic alteration
How are growth factors used by tumors?
Tumors can gain ability to produce necessary GF or develop GF receptors to increase sensitivity
What is the SIS oncogene?
β-PDGF production, ovrexpressed in astrocytomas and osteosarcomas
What is the normal behavior of a GF receptor vs the abnormal behavior?
Normal has transient activation: Dimerization and tyrosine kinase activity
Abnormal: Constitutive activation
What is ERB B2 (Her-2-Neu) and what does it indicate in breast cancer? How do we treat it?
Type of GF receptor, overexpressed often in breast cancer
It is a poor prognostic sign, indicating unresponsiveness to estrogen therapy.
Trastuzumab used to trigger a body immune response against a HER2+ cancer cell
Which cancer is c-KIT important for and what drug is used to treat it and its mechanism of action?
Affects gastrointestinal stromal tumors
Treated with Imatinib mesylate which is a tyrosine kinase inhibitor
What are signal transducing proteins?
Receive signals from receptor-ligand complex
Transiently transduce signal into organelles
What is RAS and what does a mutation do to it?
Why is it important?
What are specifc RAS variants?
Signal transducing G-protein, mutation inhibits the GTP-ase activity
Ras SNPs account for 15-20% of all tumors making it the single most common abnormality of oncogenes in tumors and a chemo target
K-Ras in pancreas, colon CA; H-Ras in bladder, kidney CA
What is c-ABL and what genetic alteration can happen?
Tyrosine kinase signal transduction, not receptor linked
t(9;22) Philadelphia Chromosome creates a bcr-abl fusion product
Results in loss of regulatory control so chronic myelogneous leukemia (CML) and Acute lymphoblastic leukemia (ALL)
What are transcription factors?
Proteins that bind to DNA and control transcription of genes (either activation or inhibition)
What is c-Myc, what disease state does it have, and what is the genetic alteration?
c-Myc: Continued expression of the MYC gene resulting in cell proliferation
Increased expression in Burkitt Lymphoma
t(8;14), attaching MYC to Ig gene.
What is n-Myc, what disease state does it have?
Amplified Myc oncogene
Amplification in neuroblastoma (25-30%)
Poor prognosis
What are cyclins?
Transient, unstable proteins that activate CDKs
What are CDKs?
Cyclin-dependent kinases which are constitutively expressed but require cyclin activation. Phosphorylate proteins necessary for transition through the cell cycle.
What is the role of cyclin D? What is a genetic alteration that results from this and the possible disease states related to this?
Activates CDK4, CycD-CDK4 complex phosphorylates Rb protein to encourage passage into S-phase
Mutation of t(11;14) results in a Cyclin D1-IgH causing overexpression of D1.
Mantle cell lymphoma, minor population of plasma cell myeloma and hairy cell leukemias.
This is detectable via cytogenetics, immunohistochem.
What are tumor suppressor genes?
Normal genes responsible for controlling cell proliferation
What is the two-hit hypothesis and the cliche example used?
Mutations in both alleles are required for oncogenesis due to the resulting loss of function.
Often given in the context of retinoblastoma, where the familial involves a germline mutation where one of the alleles already inactivated and only one more “hit” is required, while the sporatic or purely somatic form would require two “hits” still.
What is APC and what is the disease state and mechanism associated with it?
APC is a tumor suppressor gene which acts by destroying/down-regulating β-catenin.
APC mutation results in β-catenin accumulation, which complexes with TCF to stimulate transcription of many growth factors
Results in 100s of adenomas, notably in familial adenomatous polyposis (FAP)
FAP results in 500-2500 mucosal polyps in the colon of adolescents, young adults
Need to perform a colectomy to preventmalignant transformation of polyps
What is p53, what is its function, and what is the syndrome affiliated with it?
p53 is a tmor supressor gene important for cell cycle arrest and initiation of apoptosis following the detection of cell DNA damage.
Li-Fraumeni syndrome is the inheritance of a mutated p53 allele resulting in a 25-fold risk of developing cancer by 50 y/o
Mainfests with a wide variety of cancers at younger than expected ages
What are apoptosis genes? (Definition)
Genes that either downregulate (anti-apoptotic) or upregulate (pro-apoptotic) programmed cell death
What is BCL-2, what is the genetic alteration, and what disease is it affiliated with?
BCL-2 is an anti-apoptotic gene
t(14;18) resulting in the IgH-bcl-2 for follicular lymphoma
Commonly overexpressed in many lymphomas
What are the following disorders of DNA repair genes caused by?
- HNPCC
- XP
- Ataxia-telangiectasia
- Bloom Syndrome
- Faconi anemia
- Mismatch errors
- Thymidine dimers (UV)
- Ionizing radiation
- Ionizing radiation
- DNA cross-linking agents
What are the three major sources of carcinogens?
Chemicals
Radiation
Microbes
What are direct vs indirect acting chemical carcinogens?
Direct acting carcinogens:
- Highly reactive electrophilic compounds which react with DNA, RNA, protein
- No enzymatic processing
Indirect-acting carcinogens (Procarcinogens):
- Metabolism by cytochrome P-450 systems
Both ultimately target nucleic acids
Role of CYPIAI in carcinogenesis
Polymorphic gene responsible for metabolism of polycyclic aromatic hydrocarbons
10% of caucasians have highly inducible form: increased carcinogens, risk of cancer
Role of Glutathione-S-transferase in carcinogenesis
Detoxifies polycyclic aromatic hydrocarbons
50% of Caucasians have deletions; leads to increased carcinogens, risk of cancer
What are initiator vs promoters in chemical carcinogenesis?
Initiator: Chemical that causes permanent DNA mutations
- Direct and indirect acting compounds
- Damage can be either permanent (via propagation) or repaired
**Promoter: **Nontumorigenic chemial that enhances the proliferation of mutated cells; effect is reversible
Examples: Phorbol esters, hormones, phenols, bile salts, alcohol
DNA + Initiator = Mutated DNA
Mutated DNA + Promoter = Replicated Mutated DNA
What are polycycline aromatic hydrocarbons? (Structure, sources,implicated cancers)
Potent chemical carcinogen initator made of 3+ fused benzene rings
Sources: Coal/oil combustion, iron/steel foundaries, tobacco smoke
Cancers: Lung, Bladder, Laryngeal/oral cavity
What are the two main forms of radiation involved in carcinogenesis and what kinds of cancer are they affiliated with?
Ionizing radiation: X/gamma rays
Exposure from radiologic exams, occupational exposure, nuclear accidents/bombs
Leukemia, breast, colon, thyroid, lung
**UV light: **UVA, UVB, UVC result in formation of pyrimidine dimers
Affects nucleotide excision pathway, xeroderma pigmentosum, and mutations in protooncogenes
Associated with skin cancers: Basal cell carcinoma, Squamous cell carcinoma, Melanoma
What are the main mechanisms used by microbes for oncogenesis?
Viral genomic oncogenesis: Overexpression of viral proteins which affect host cell growth or disruption of protooncogene
Examples: E6/7 proteins of HPV, EBV, HBV, HTLV-1
Stimulation of host inflammatory response: Causes regeneration
HBV/HCV, H. pylori, Schistosoma hematobium and Chlonorchis sinesis
What cancers are associated with EBV?
Burkitt lymphoma, endemic and HIV-associated
Post-transplant lymphoproliferative B-cell disorders
B-cell lymphomas in immunosupressed patients
NK/T-cell lymphoma, nasal type
Hodgkin lymphoma
Nasopharyngeal carcinoma
What cancers are associated with HPV?
Verruca vulgaris, plantaris
Squamous papillomas of oral cavity and larynx
Squamous dysplasia of female and male GU tract, anus, larynx
Condyloma accuminatum of female and male GU tract, anus
Carcinoma in situ of female and male GU tract, anus, larynx
Squamous cell carcinoma of female and male GU tract, anus, larynx
What is HPV’s mechanism of oncogenesis, risk types, and diagnosis procedure?
**Mechanism: **Integration site causes loss of regulation of E6 and E7 leading overexpression; E6 inhibits p53, E7 inhibits p53, p21, Rb
**Risk types: **Low risk - HPV 6,11; High risk- HPV 16,18,31,33
Corresponds to affinity differences of E6/7
**Diagnosis: **Viral cytopathic effect, immunohistochemistry of p16, molecular studies
What are HBVs mechanism of carcinogenesis?
- Cirrhosis
- Integration of HBx protein which inhibits p53
How does cirrhosis lead to hepatocellular carcinoma?
Regenerative nodular hyperplasia
Based on normal hyperplastic response to damage
Increased risk of genetic abnormalities with continued proliferation
Spontaneously arises, but can be carcinogenically induced (e.g. Alfatoxin)
What is H. pylori’s mechanism of carcinogenesis and which tumors is it implicated in?
Inflammatory response causes constant regeneration to metaplasia, dysplasia, carcinoma (Gastric adenocarcinomas)
Polyclonal expansion in extranodal marginal zone of mucosa associated lymphoid tissue (MALTs) can select for clonal population with additional mutations for MALToma
