Molecular Oncogenesis Flashcards
What is the molecular genetic basis of cancer?
A combination of acquired (somatic), inherited (germline), and other infections/epigenetics all contribute to the formation of cancer
**Nonlethal genetic damage lies at the heart of carcinogenesis
What are the characteristics of oncogenes?
- Drug targets
- One mutated gene (dominant; only need to lose one copy to lose function) “DRIVER MUTATION”
- Constitutive activation (fuel)
- Growth factors/receptors
- Signaling molecules
- Transcription factors
Contrast a proto-oncogene and oncogene
Most oncogenes began as proto-oncogenes, normal genes involved in cell growth and proliferation or inhibition of apoptosis. If normal genes promoting cellular growth, through mutation, are up-regulated, (gain of function mutation) they will predispose the cell to cancer and are thus termed oncogenes
What are the characteristics of tumor suppressor genes?
- Two mutated genes (recessive; need to lose BOTH copies for loss of function) “Loss of heterozygosity”
- Loss of function (brakes)
- Tumor suppressors (TP53)
- Cell cycle controllers (RB)
What are two examples of small genetic lesions?
**They are simple to detect
- Single nucleotide variant (e.g. BRAF, KRAS, NRAS, EGFR)
Can cause CRC, thyroid, melanoma, lung - Insertion/deletion “Indel” (e.g. EGFR -> lung cancer)
What are two examples of large genetic lesions?
**Complex to detect
- Copy number variants (e.g. HER2 amplification, 1p/19q deletion) Causes breast cancer/glioma
- Structural variants (translocations e.g. EWSR1 -> ewing sarcoma)
What are the types of single nucleotide variants?
- Silent (AA not changed; clinically benign and not reported)
- Missense (AA changed; benign, uncertain, or pathogenic; MD determines if reported)
- Nonsense (Stop codon instead of AA; pathogenic and always reported)
What is the usual tumor progression? How long does this take?
Transformation of normal to tumor cell -> progression -> proliferation of genetically unstable cells -> tumor cell variants; heterogeneity -> clonal expansion of surviving cell variants
**decades while cancer develops
**only ~2 yrs from invasive presentation to death
**clinically detectable cancer ~6 months prior to death for invasive pancreatic cancer
What are driver mutations?
Mutations that alter the function of cancer genes (oncogenes), primarily responsible for the cancer phenotype
**represent therapeutic targets
What is a passenger mutation?
Acquired mutation that does not contribute to cancer phenotype but may synergize with driver mutations
Contrast the different ways receptors can affect cancer
- Normal receptors have transient activation (“lights on and off”)
- Mutant receptors are constitutively activated (“lights always on”)
- Overexpression of receptors results in increased sensitivity to growth factors (“lights turn on easier/need less stimulation”)
**tumors can synthesize and secrete their own GF (paracrine loop)
Describe the major characteristics of the ErbB1 gene
- EGFR mutation; predicts responsiveness to anti-EGFR TKI
- mutation causes lung cancer
- overexpressed in many cancers
- targeted drug therapy= erlotinib
Describe the major characteristics of ErbB2
- Also called Her2/Neu
- Amplification in breast cancer; poor prognostic sign
- Predicts lack of response to estrogen therapy
- Targets drug therapy= trastuzumab
What is KIT?
KIT mutation is seen in GIST (GI stromal tumors) and can be specifically targeted by the drug imatinib (a CKIT tyrosine kinase inhibitor)
What are signal transducing proteins?
- couple receptors to nuclear targets
- mutations “short circuit” the receptor
- constitutive signalins is observed in cancer
- E.g. RAS, BRAF
What is the rule of thumb for ATP and GTP hydrolysis?
ATP hydrolyzed for work
GTP hydrolyzed for signaling
Describe the RAS oncogene family
RAS are GTP binding proteins; mutations affect GTP binding/hydrolysis (lock RAS in permanent activation)
Describe the effects of mutations in BRAF and 2 drugs used for targeted BRAF therapy
BRAF is a ser/threonine protein kinase that is activated by Ras
There are mutations in BRAF in 100% of hairy cell leukemias and 60% of melanomas
**Targeted BRAF therapy by vemurafenib and dabrafenib
Describe “oncogene addiction” and one example
When a cancer is dependent on the fusion/crossing of genes;
E.g. Normally ABL oncogene (a non-receptor tyrosine kinase) is at the end of a normal chromosome and not expressed… cross-over switches ABL from 9 to 22 and allows its constitutive expression thanks to the BCR locus ->
Chronic myelogenous leukemia (CML) or
Acute lymphoblastic leukemia (ALL)
**Targeted therapy= imatinib
How does the G1-S checkpoint work? (what protein?)
The RB protein is either…
-
hypophsophorylated
- stimulated by growth inhibitors such as TGFbeta/p53
- keeps transcription factor E2F near it, preventing S phase gene expression -> cell stays in G1
-
hyperphosphorylated
- stimulated by growth factors such as EGF/PDGF
- allows E2F to dissociate, travel to DNA and allows S phase gene transcription -> cell enters S phase)
What is the main homeostatic balance that is broken down in cancer?
Cell cycle control (RB) versus DNA damage sensor (p53)
What is the APC gene?
It negatively regulates the WNT pathway by promoting the degradation of beta catenin leading to no celllular proliferation
What proteins are commonly mutated in gliomas?
Isocitrate dehydrogenase 1/2 (IDH1 and IDH2); normally catalyze isocitrate -> alpha KG + NADPH
*TET inhibits DNA methylation, 2-HG inhibits TET, IDH mutation upregulates 2-HG -> increased DNA methylation
**NADPH helps glutathione formation and normally provides protection from oxidative stress… glioma mutations are all missense
What is the mechanism by which EBV can cause cancer?
Normally, latent Epstein Barr Viral infection leads to polyclonal B cell expansion which is self limiting via CTLs
**B cells can undergo mutation (e.g. MYC translocation) and continue to replicate uncontrollably -> burkitt lymphoma
