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What are oncogenes?
- oncogenes encode genes whose protein products stimulate cell growth and proliferation
- ex. growth factors, growth factors receptors, tyrosine kinases, secondary messengers, nuclear transcription factors
What are proto-oncogenes?
- normal form of the gene involved in induction of cellular proliferation, but in controlled manner
- alteration of proto-oncogene -> uncontrolled growth
What are the 3 ways proto-oncogenes can become oncogenes?
- 1. point mutation - leads to production of protein that functions in an uncontrolled manner resulting in unregulated cell proliferation
- 2. reduplication or amplification of DNA -> over-expression of proto-oncogene protein product
- 3. chromosomal translocations -> over-expression of proto-oncogene or structural changes
Oncogenes act in dominant/recessive fashion?
dominant - only 1 allele needs to be altered to produce stimulatory effect on cellular proliferation
Describe the growth factor oncogene.
- c-sis proto-oncogene - encodes for beta chain of platelet-derived growth factor (PDGF)
- in tumors, this protein is over produced
- tumors have receptors for PDGF
- result = constant stimulation by growth factor that the tumor itself produces
Describe the growth factor receptors oncogenes.
- overexpression of EGFR secondary to amplification of the gene seen in cancer
- also can be from point muation
- these tumors are often distinct in respect to organ and cell type when compared to amplication
Describe the example of secondary messenger oncogene.
- 30% of human tumors contain ras oncogenes.
- ras proteins = G protein = signal transduction proteins that transduce signals when bind GTP -> hydrolyzes GTP to GDP
- mutant ras proteins can hydrolyze GTP to GDP
- problem - problems in terminating signal transduction
- result - inappropriate stimulatory signals to cell
Describe nuclear transcription factors.
myc proto-oncogenes activate the transcription of a number of genes needed for cellular proliferation
what does tumor suppresor genes do?
regulate the cellular proliferation
What happens when tumor suppresor gene function gets altered?
muations affecting expression or function of tumor suppresssor genes create state of uncontrolled proliferation
Tumor suppressor genes have dominant or recessive mode of action?
- recessive - protein product from 1 allele is general sufficient to provide normal control of cellular proliferation
- both genes must be altered to produce transformation of cell, but alternation of second allele relatively common
What are the possible ways of eliminating normal Rb gene (tumor supressor gene)?
- nondisjunction and duplication
- mitotic recombination
- gene conversion
- point mutation
What are the 3 examples of tumor suppressor genes?
Two primary tumor suppressors are the products of what?
- retinoblasoma gene
- p53 gene
the rate limiting step of tumor suppressor gene is production of the first functionally abnormal allele. The remaining normal allele only needs to be ______.
- silenced (in contrast to prot-oncogenes which must gaina activity)
- relatively high frequencey
- once every 103 vs. more than 106 cell divisions for sequence mutation
How is the loss of p53 gene leads to cancer?
- function of p53 = arrest cells in G1 when DNA damage has occurred
- arrest gives the cell time to repair DNA damage
- point mutations alter function allowing unchecked progress through cell cycle
- homozygous loss of p53 seen in nearly 1/2 of all malignancies
What is Rb and how does its alteration affects cells?
- retinoblastoma produces a protein that prevents cells from leaving G1 or G0 and entering the cell cycle
- phosphorylated forms of Rb bind and inactivate transcription factors that are responsible for initiating transcription of cell cycle genes
- mutant form of Rb - unable to bind and inactivate transcription factors
- tumor develops when both genes are altered
What does Bcl-2 do?
- it is the primary control of apoptosis
- normal function - prevents cells from undergoing apoptosis
- overexpression leads to abnormal survival and proliferation of cells
- activations occurs when chromosomal translocation places it near the immunoglobulin heavy gene promoter in Burkitt's lymphoma
- "immortalization" of cells that normally undergo apoptosis
What is cellular senescence?
- genetic material lost from the end of chromosomes with each division eventually signals senescence (deterioration with age)
- abnormal expression of telomerase in cancers prevents this loss -> extended lifespan of cell
what is autosomal dominant hereditatry cancer?
- phenotypic expression of increased cancer incidence due to inheritance of single mutated gene allel
- pattern of dominant inheritance shows classic Mendelian features with 50% of offspring affected and consistent occurrence in every generation
Tumor suppressor genes associated with _____ mode of action but _____ pattern of inheritance.
Describe hereditary retinoblastoma. Mode of action? Percentage of germline mutation the develop tumor? Percentage that develop bilateral retinoblastoma. Average age for development of tumor? Increase of decrease incidence of other tumors?
- 1. only single allele needs somatic mutation
- 2. 80-80% with germline mutation develop tumor
- 3. 90% develop bilateral retinoblastoma
- 4. Average age at development of tumor - 2 yr
- 5. Increased incidence of other tumors
Describe sporadic retinoblastoma. Mode of action? overall incidence? Bilateral?
- 1. single cell with somatic mutation of Rb plus inactivation of other allele
- 2. overall inciden < 1/20,000
- 3. never bilateral
Describe familial Adenomatous Polyposis (FAP). What type of mutation is this? Symptoms? % develop colon cancer by 50 y.o? Average age of diagnosing cancer?
- 1. germline mutation in APC gene
- 2. Somatic mutations in unaffected allele causes growth of hundreds of adenomas in young adults
- 3. 100% develop colon cancer by 50 y.o.
- 4. average age at diagnosis of cancer = 40 y.o
Describe sporadic colon carcinoma.
- 1. somatic mutations of both APC genes must occur in a single ceel
- 2. additional mutations must occur in only one of a few adenomas for cancer to develop
- 3. average age at diagnosis of cancer = 65 y.o.
Describe autosomal recessive hereditary cancer. Phenotypic expression? pattern of recessive inheritance?
- phenotypic expression of increased cancer incidence due to inheritance of 2 mutated gene alleles (one of each parent)
- pattern of recessive inheritance shows classic Mendelian features of rare incidence, only 25% of offpsring of crossed heterozygotes affected and generations frequently skipped
genes altered for autosomal recessive hereditary cancer are invovled in activities such as what?
- genomic instability
- anti-tumor immune surveillance, enzymatic conversion of chemicals to carcinogens
What are some of autosomal recessive hereditary cancer syndromes?
- xeroderma pigmentosa (genomic instability, carcinogen hypersensitivy)
- Fanconi's Anemia (genomic instability)
- Ataxia-telangiectasia (genomic instability, defective immunosurveillance, carcinogen hypersensitivity)
- severe combined immunodeficiency (defective immunosurveillance)
variety of tumors for recessivley inhereited cancer syndromes but _____ are more frequent than solid tumors.
What are the characteristics that enhance malignant potential and are associated with tumor progression?
- 1. enhanced rate of growth
- 2. decreased susceptiblity to anti-neoplastic drugs
- 3. decreased susceptiblity to host defenses against cancer.
- 4. decreased dependence on exogenous growth factors/hormones for growth.
- 5. increased ability to recruit blood supply (angiogenesis)
- 6. enhanced ability to invade and metastasize.
What happens during invasion?
- facilitated by loss of surface proteins that "glue" cells together
- acquisition of increased # of receptor components that facilitate adherence to extracellular matrix components
- production of enzymes that will chew thru extra-cellular matrix and eventually into blood or lymphatic vessel
- acquisition the ability to migrate thru the digested extra-cellular matrix
What happens during metastasis?
- once in circulation, acquisition of various membrane proteins by tumor cells - let them associate with each other & w/ platelets to form tumor emboli
- membrane proteins - help tumor cells (in form of tumor emboli) to adhere to vascular endothelial cells of specific organs
- once adhere, tumor cells chew thru vessel wall into surrouding tissue and establish metastatic focus
What is angiogenesis?
- the growth of new vasculature - needed for tumor growth
- supplies high metabolic needs of tumors
Tumors do not exceed what size w/o recruiting additional blood vessels?
1mm in diameter
What determines the net angiogenic activity?
balance between pro-angiogenic and anti-angiogenic factors
Angiogenic factors are potential targets for what?
diagnosis and treatment of tumors
metastatic capacity influenced by what?
angiogenic activity in tumor
What are tumor specific antigens? what does it bind to? and leads to what?
- mutant forms of normal protein made by tumor cells
- bind to class I MHC and form complex
- cytotoxic T cells see it on surface of tumor cell, see it as foreign, and body tries to kill it
what are the host defense against tumors?
- cytotoxic T cells
- natural killer cells
What are tumor mechanisms of evasion (2)?
- mutations leading to decreased class I MHC expression
- mutations leading to secretion of substances that suppress immune response
How do antibody protect body against tumors?
antibody induce complement mediated cell lysis
For molecular diagnostics of cancer, how should we diagnose neoplastic disease?
a genetic abnormality is so characteristic that demonstration is recommended or required for establisment of diagnosis
CML (Chronic myelogenous leukemia) is characterized by what? where was it translocated?
- characterized by Bcr-Abl translocation between chromosome 9 and 22
- present in >95% of CML cases
- use FISH cytogenetic test to establish diagnosis
Describe JAK2 V617F diagnostic test.
- JAK2 is commonly mutated at amino acid position 617 in PV, ET, and PMF
- JAK2 V617F mutation is present in 95% of PV and about 40% of ET and PMF cases
- JAK2 V617F Mutation is NOT present in solid tumors, reactive myeloproliferative states or lymphoid malignancies
Prognosis for cancer - a variety of assays can give info about the expected behavior of a tumor. Ex of Lung and breast cancer.
- Lung cancer with EGFR mutations are associated with longer survival than those w/o
- HER2 + breast cancers are more aggressive - possibly responseive to Herceptin
Describe some biochemical assays use as prognosis.
- Tissue specific factors may be released from tumors of a specific organ (Prostate specific antigen...)
- disadvantage - can be a screening tool but inflammation and other process can lead to an increase level (too many false positives)
- advantage - strong senitivity (false negative are uncommon ) so use as screening tests or to detect recurrence of disease
Describe the minimal residual disease detection. What is the method used? What is is use for? Advantages? Disadvantages?
- method - PCR detection of very small amounts of malignant cells
- use for - evaluation for effectiveness of treatment to see when additional therapy is needed
- Disadvantages - easy to get a false positive
- ex. Bcr-Abl translocation to track CML
- tumor specific Ig rearragements to track lymphoma prognosis
EGFR targeted therapy in lung cancer - dramatic responses EGFR inhibitors can be seen in lung cancer (about 15-20% of patients). Presence of activiating mtuationsin EGFR is?
- predictive of response
- activiating mutations are gnerally asssociated with alterations in receptor conformation causing constitutive activity in internal tyrosine kinase domain (no ligand interaction needed)
rare mutations such as T790M is associated with what?
resisitance to EGFR inhibitor therapy
in colon cancer, bypass of EGFR pathway may lead to what? what mutations?
- lack of sensitivity to EGFR inhibitors
- mutations in KRAS are present in 40% of colon cancers and indicate resistance to EGFR inhibitors
- tumors with wild-type Krase are responsive to EGFR inhibitors
What is patient specific tumor profiling?
- characterize the expression pattern of the entir genome in given tumor
- allow ID of primary characterisitc of lesion and eventually allow us to predict tumor behavior and choose very effective therapies in patient specific manner
What is a hurdle in patient specific tumor profiling?
data management - huge amount of data
For molecular profiling, what is the gene expression microarray analysis?
- RNA expression levels indicate overactive/underactive pathways for every gene in genome
- Identity of gene is established by sequence of probe present at the spot on the microchip from which signal is generated
FOr molecular profiling, what is proteomic profile?
- high resolution mass spectrometry provides very specific patterns of protein expression
- identity of characteristic proteins not given but patterns have proven to be specific