Tumor Oncogenesis Flashcards
What 3 things are the molecular basis for cancer
- acquired mutations (somatic)
- inherited mutations (germline)
- other (infections, epigenetics)
NOnlethal genetic damage lies at the heart of carcinogenesis
Mutation + Cancer gene=_______
initiating event
most mutations occur randomly and are clinically insignificant
the genme is very big and cancer genes are a fraction of the genome
Describe the basic molecular pathology of cancer
genetic variants in DNA and RNA lead to diagnosis prognosis and treatment
What are oncognenes?
- one mutant gene (domniant)
- constitutive activation (fuel)
- growth factors and receptors
- signaling molecules
- transcription factors
- “Driver mutation”
What are tumor suppressor genes?
two mutated genes (recessive)
loss of function
tumor supressors
cell cycle controllers
*loss of control on roliferation and loss of DNA damage response
loss of heterozygosity
Genetic lesions=____________
Variants!
What are small genetic lesions and what do they cause?
- single nucleuotide variant
- insertion/deletion (indel)
- simple to detect
*
What are large genetic lesions and what do they lead to
- copy number variants, structural variants
- complex to detect
What simple genetic lesions occur at the nucleotide level?
single nucleotide variant
insertions or deletions “indels”
**these are small/simple genetic lesions**
WHat is a single nucleotide variant?
- change the codon sequence
- may alter the amino acid in protein
- may contribute to the cancer phenotype
*
What are 4 classes of a single nucleotide variant
- no mutation
- silent mutation: clinically benign, not reported
-
missense: benign, uncertain or pathogenic
- MD determines if reported
- Nonsense mutation: pathogenic, reported
What genetic variations occur at the structural level (chromosomes)
large/complex genetic abberations
- fusion genes and chimeric proteins (SV)
- gains and losses of chromatin
what are the “driver mutations”
- mutations that alter the function of cancer genese
- primarily responsible for the cancer phenotype
- represent therapeutic targets
WHat are passenger mutations?
- acquired mutation that does not contribute to cancer phenotype
- may synergize with driver mutations
Tumors can synthesize and secrete their own ______
growth factor! this is called a paracrine loop
- Glioblastoma: synthesis PDGF and PDGFR
- Sarcoma: TGFa and TGFaR
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
What are two growth factor receptors that are examples of targeted drug therapy? What drugs target each?
ErbB1 (EGFR)
- overexpressed (many cancer)
- mutated (lung cancer)
- predicts responsiveness to anti-EGFR TKI
- Erlotinib
ErbB2 (her2/Neu)
- amplification in berast CA
- poor prognostic sign
- predicts lack of response to estorgen therapy
- Trastuzumab
Other than ErbB1 and ErbB2 growth factors what is another growth factor mutation? and where is this commonly seen?
KIT mutation
gastrointestinal stromal tumors (GIST)
how do we treat a KIT mutation?
CKIT tyrosine kinase inhibitor
drug name: Imatinib (Gleevec)
Mutations don’t need to be directly in DNA they can be in ________
signal transducing proteins
what are signal transducing proteins and what are two examples that are commonly mutated
- couple receptor to nuclear targets
- mutations “short circuit” receptor
- cancer=constitutive signaling
- ex: RAS, BRAF
what is RAS, what does mutation cause?
RAS is GTP-binding proteins
mutations affect GTP binding or GTP hydrolysis
Lock RAS in permanent activation: oncogene
What is BRAF? WHat kind of cancers result when mutated?
serine/threonin protein kinase
hairy cell leukemias
melanomas
what drugs are used to treat 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. bcr is a promotr. this fusion leads to actiavtion of everything downstream of the promotor. (loss of regulatory control/constituitively active)
- bcr-abl t(9;22)
what cancers are associated with a philadelphia chromosome fusion oncogene? WHat is the treatment
- ABL non-receptor tyrosine kinase
- Chronic myelogenous leukemia
- Acute lymphoblastic leukemia
- treatment: Imatinib (Gleevec) it is the poster child for this therapy bc it was caused by a single gene mutation “oncogene addiction”
what is oncogene addiction
when a cancer is caused by a single mutation in a single gene and treating that one mutation cures the cancer ex: philadelphia chromosome, why it is great for imatinib treatment
What influence do oncogenes have on transcription factors? what are some examples?
- TFs are the endpoint of signal transduction
- oncogenes lead to continuous stimulation of TFs which drives expression of growth promoting genes
- ex: MYC, MYB, JUN, FOS, REL
What is Myc? What results from activation of MYC gene
Myc is a master transcriptional regulator of cell growth.
mutations lead to:
- upregulation of Cyclin D (cell cycle progression)
- other pro-growth genes that allow cells to divide uncontrollably
WHat type of cancer is associated with Myc mutations?
Burkitt Lymphoma