16 - Molecular Oncogenesis Flashcards
What three things are the molecular genetic bases of cancer? Why are these important?
- Acquired mutations (somatic)
- Inherited mutations (germline)
- Other (infections, epigenetics)
Nonlethal genetic damages lie at the heart of carcinogenesis.
Mutation + cancer gene = _____? How does this ocur?
Initiating event.
The gene is big and rarely include cancer genes. Mutations occur randomly and are currently insignificant.
What is the molecular pathology of cancer?
Mutations in DNA and RNA lead to genetic variants and thus lead us to the diagnosis, prognosis, and treatment.
What are characteristics of an oncogene? What are examples?
One mutant gene (dominant,“driver mutation”) with constituitive activation (gasoline the tumor uses to grow).
Examples: growth factors and receptors, signaling molecules, and transcription factors.
Drug targets.
What are characteristics of tumor suppressor genes? What are examples? What happens when they’re mutated?
Genes that cause loss of funciton for tumors (“brakes”).
Examples: Tummor suppressers (p53) and cell cycle controllers (RB)
Mutations in tumor suppressor genes cause loss of control on proliferation and loss of DNA damage response.
Loss of heterozygosity (loosing both tumor suppressor genes) causes loss of function.
What type of mutations are small genetic lesions?
Single nucleotide variants such as insertions or deletions (indel)
Simple to detect
What type of mutations are large genetic lesions?
Copy-number varients and structural variants.
Complex to detect.
What is another term for a genetic lesion? Are these mutations?
A variant.
Not all variants are mutations, variants are just disagreements with a reference sequence.
What genetic lesions occur at the nucleotide level?
Single nucleotide variants (SNV) and Insertions or deletions (indel).
These are are small/simple genetic lesions.
What is a small nucleotide variant and what are the consequences?
Chancein the codon sequence.
May alter the amino acid in protein, may contribute to the cancer phenotype.
What are the four types of single nucleotide variants?
- No mutation
- Silent - clinically benign/not reported
- Missense - benign, uncertain, or pahtogenic
- Pathogenic - reported
What types of mutations occur at a structural level (chromosomes)
Large/complex genetic aberrations:
- Fusion genes and chimeric proteins
- Gains and losses of chromatin
What are driver mutations? What are passenger mutations?
Driver: mutations that alter the function of cancer genes, primarily responsible for the cancer phenotype and represent therapeutic targets.
Passenger: acquired mutation that does not contribute to cancer phenotype, may synergive with driver mutations
Describe the process of tumor progression and generation of heterogeneity? What is the significance of this in treatment?
- One cell aquires mutations that it needs to grow and survive.
- Tumor cell variants grow to form a polyclonal mass of cells.
When you treat, only a fraction of cells will respond to the drug while other subclones can still grow out.
(You need to treat the most aggressive met cell types)
About how long does it take for a tumor cell to become an invasive tumor? From the time it becomes an invasive tumor, how long does it usually take to kill the patient? When does it usually become clinically apparent?
Birth-invasive: ~decade
Invasive-death: ~2 years
Clinically apparent: ~6mo before the patient dies
What is function and activity of growth factor and growth factor receptor?
What happens when they are mutated?
Growth factor receptors are RTKs that, upon GF binding, dimerize and cause the catalytic domain to come together to form a docking site for intracellular mediators.
Normal receptors: transient activation
Mutant receptors: constituitively activated
Overexpression of recptors causes increased sensisitivy to growth factors
Tumors can synthesize and secrete their own _____, and this is called paracrine loop.
What are examples of this?
Growth factor
Glioblastoma: synthesis of PDGF and PDGFR
Sarcoma: synthesis of TGFa and TGFaR
What are two growth factor receptors that are examples of targeted drug therapy? What drugs target each?
1. ErbB1 (EGFR): overexpressed in many cancers and is mutated in lung cancer.
- predicts responsiveness to anti-EGFR tyrosine kinase inhibitors
- Erlotinib
2. ErbB2 (Her2/Neu): amplified in breast CA
- poor prognostic sign, predicts lack of response to estrogen therapy
- Trastuzumab
Other than ErbB1 and ErbB2, what is a third growth factor receptor that is an example of targeted drug therapy? How can it be treated? What is the most common location of this mutation?
KIT mutation: seen in gastrointestinal stromal tumors (GIST) - most commonly in exon 11.
- Becomes activated like EGFR when mutated
- Treated with CKIT tyrosine kinase inhibitor: Imatinib (Gleevev)
What are signal transduction proteins? What happens when they have a mutation?
Molecules that couple receptor to nuclear targets.
Mutations “short circuit” the receptor.
Cancer resutls when these have mutations and become constituitively activated.
Examples: RAS and BRAF (commonly mutated)
Molecules that hydrolyze ____ are usually doing work, while _____ is usually reserved for signaling.
ATP for doing work
GTP for signaling
What is RAS? What happens when it has a mutation?
RAS is a GTP-binding protein.
Mutations in RAS affect GTP binding or GTP hydrolysis and cause RAS to be locked into permanent activation (oncogene)
What is BRAF and what results from mutations in BRAF?
Serine/threonine protein kinase that is mutated in 100% of hair cell leukemia and 60% of melanomas.
What drugs can be used for targeted treatment of cancer caused by a BRAF mutation?
Vemurafenib
Dabrafenib
What is a philadelphia chromosome fusion oncoprotein? What causes this?
Cytosolic tyrosine kinase that gets fused to BCR, which is a promotor. This fusion leads to activation of everything downstream of the promotor (constituitively activated, loss of regulatory control).
Bcr-abl t(9:22) - t means translocation
What cancers are associated with philedelphia chromocome fusion oncoprotein? What is the treatment?
Acute lymphoblastic leukemia (ALL)
Chronic myelogneous leukemia (CML)
Poster child for targeted therapy because it’s caused by single gene translocation.
Treat with Imatinib (Gleevec)
What is oncogene addiction?
When cancer is caused by a single mutation in a single gene, and treating that one mutation cures the cancer.
What impact do oncogenes have on trasncription factors? What are some examples of transcription factors commonly mutated in cancer?
TFs are the endpoint of signal transduction.
Oncogenes lead to continuous stimulation of TFs and drive expression of growth-promoting genes.
Exp: MYC, MYB, JUN, FOS, REL
What is MYC and what results from activation of MYC gene?
MYC is a master transcriptional regulator of cell growth.
Mutation results in upregultion of cyclin D (cell cycle progression), and other pro-growth genes that allow the the cell to enter the cell cycle and divide uncontrollably.
What are the transforming effects of HPV E6?
- Activate TERT to cause increased telomerase expression
- Inhibit p53
Results in immortalization and increased cell proliferation
What is the function of Bcl2 and how does it relate to follicular lymphoma?
Bcl2 stops BAK/BAX from activating the intrinsic mitochondrial apoptotic pathway (Bcl2 stops apoptosis).
Follicular lymphoma = overexpression of bcl2.
Overexpression of bcl2=no apoptosis and accumulation of lymphocytes in a follicle.
How are immune checkpoint inhibitors involved in cancer treatment? What is an example of a drug that does this?
Checkpoint inhibitors put T cells into senescence (PD1 binds PDL1 on tumor causing senecence)
Drugs block checkpoint inhibitors so T cells can be activated and fight tumors (nivolumab).
What is Human T Cell Lymphotrophic Virus-1 (HTLV-1)?
RNA virus that targets CD4+ T cells.
Activates TAX gene causing activation of cytokine genes in host T cells. T cells release cytokines which stimulate macrophages to release mitogens (which activate T cells).
This establishes a paracrine loop to lead to proliferaiton.
What are two classifications of carcinogenic compounds?
- Initiator: causes permanent DNA mutations directly or indirectly
- Promoter: nontumorigenic chemical that enhances the proliferation of mutatel cells (reversible)
Without a promotor, the initiator is unlikely to cause cancer
