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46 Cards in this Set
- Front
- Back
Why understand cancer genetics?
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Diagnostics, prognostics, stratification, therapeutic targeting
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Strategy to prevent recurrent cancer
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Targeted cancer treatment based on individual gene expression patterns
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Malignant cell transformation
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State change from normal cell to a cancer cell; Malignant cancer cells invade neighboring tissues, enter blood vessels and metastasize to different sites; caused by several mutations, not just one.
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Benign hyperplastic cells
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Tumor cells grow only locally and cannot spread by invasion or metastasis
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Normal cell division vs. Cancer cell division
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Normal: cell damage without repair--> apoptosis; Cancer: mutation--> passes on to daughter cells, 2nd mutation--> passes on to daughter cells, 3rd mutation---> uncontrolled growth
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Common features of cancer cells (12)
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(1) Sustained angiogenesis (2) tissue invasion & metastasis (3) Evading apoptosis (4) Self-sufficiency in growth signal (5) insensitivity to anti-growth signals (6) limitless replicative potential (7) DNA damage stress (8) Oxidative stress (9) Mitotic stress (10) Proteotoxic stress (11) Metabolic stress (12) Evading immune surveillance....basically cancer cells live a stressful life
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Causes of cancer (8)
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(1) Viruses & bacteria- example: Hepatitis B, cervical cancer (Gardasil vaccine) (2) Chemical exposure (3) Radiation exposure (4) Hereditary (5) Diet (6) Hormones (7) Oncogene & Tumor suppressor mutation (8) Random accumulation of mutations due to DNA replication & oxidative stress--this is why we can't prevent all cases because we can't stop mutations from happening
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Somatic mutations
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Occur in nongermline tissues; are nonheritable
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Germline mutations
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Present in egg or sperm; are heritable- all cells affected in offspring; cause cancer family syndrome
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Cancer cells have mutations in:
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primarily: oncogenes, tumor suppressor genes, DNA repair genes;
also: cell death genes, cell signaling genes, cell checkpoint genes, cell senescence genes, cell differentiation genes, metastasis/invasion genes |
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Oncogene
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gene mutated in cancer, whose increased expression or activity drives cell transformation; these get turned on in cancer
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Tumor suppressor
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gene mutated in cancer, whose decreased expression or activity allows cell transformation; are inactive in cancer
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Stages where mutations can occur
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growth factors, receptors (Her2, EGFR), signaling enzymes (Ras, Raf), transcription factors (Myc, NF-kB)
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Gene amplification
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leads to overexpression of gene which leads to more signaling than you should actually be getting, leads to insensitivity
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Translocation of genes
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example: in leukemia, Bcr-Abl genes, leads to higher expression of abl
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Genes that act like brake pedals
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Tumor suppresor genes; can inhibit at each stage: receptor--->signaling enzymes-->transcription factors; also if the recycling of receptors is inhibited, this inhibits receptor
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Tumorigenesis
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Caused by the loss of BOTH copies of tumor suppressor (called loss of heterozygosity event)
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p53
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A tumor suppressor gene that triggers cell suicide and regulates apoptosis; usually mutated in cancer cells which causes inappropriate cell survival; looking for a way to change mutant back to non-mutant
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Oncogene Cooperation
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Interaction between oncogene mutations causes the emergence of malignant transformation; cancer doesn't happen with just one mutation of oncogene or of one tumor suppressor; 3-5 mutations cause cancer; the cooperation drives malignant transformation; Just Ras mutation or just Myc mutation doesn't cause cancer, but mutation in both causes cancer
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Cancer genome landscapes
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Show how many mutations are in each gene; certain genes have many mutations (p53)
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Predicted rates of colon cancer based on 1, 2 or 4 mutations
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If only one mutation caused cancer, there would be a linear relationship between age and risk of cancer. The more mutations needed to cause cancer, the more curved the graph becomes. Comparing to actual data shows that 3-5 mutations cause cancer
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Cancer cells have complex architecture
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They rely on changes in effectors which underlies malignant transformation:
A +B -----> invasion, growth, angiogenesis, survival ---> transformation; NOT: A ----> Invasion, angiogenesis ---> transformation; B -----> survival, growth -----> transformation; |
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Two functions of Myc; Cooperation of Myc with Bcl-2
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(1) Myc-Max ----> Proliferation
(2) Myc-Max -----> Death; inhibited by Bcl-2 & IGF1; In normal cells, Myc causes cell death |
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Cooperation of mutant Ras/Raf with p53
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-Promotes cell proliferation
-Ras/Raf + p53 ----> p21 -----| cyclin cdk; (p21 inhibits growth arrest) -Ras/Raf alone ------------> cyclin cdk on |
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Cooperation response genes
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Essential mediators of malignant transformation synergistically (more than additive) regulated in response to the combination of loss-of-function mutant p53 and constitutively active Ras. Changes in apoptosis, transcription, signaling, metabolism, & adhesion.
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What do DNA tumor viruses do?
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They alter cellular gene function; example: HPV, Epstein-Barr, chronic infection
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What do transforming retroviruses do? What did Bishop & Varmus find?
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They acquire and transmit cellular DNA.
B & V showed that gene sequences in transforming retroviruses were homologous to sequences in cellular DNA; Example: Rous Sarcoma virus (Src); myelocytomatosis virus (myc); |
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p53: tumor suppressor or oncogene?
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Oncogene evidence: (1) adding anti p53 to mouse 3T3 cells causes growth arrest (2) in rat embryonic fibroblasts, p53 cDNA immortilizes cell and p53 cDNA + Ha-Ras causes transformation into tumor. Experiment lacks loss of function control.
Tumor suppressor evidence: Mutant (& inactive) p53 found in tumor cells, the 2nd allele is either lost through loss of the chromosome, or inactived by deletion. This seems to confer a selective growth advantage to cells Answer: wild type p53 is a tumor suppressor, mutant is an oncogene. Why was there oncogene evidence? the cDNA was for a mutated p53 |
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p53 and cancer
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1- p53 mutations can be found in 50% of human cancers, but their penetrance is highly heterogeneous, as reflected by the diverse remaining transactivation activity that ranges from O to 100%. 2- Various DNA viruses, such as SV40, HPV or adenoviruses, encode proteins that target p53 protein. 3- In inflammatory breast cancer and neuroblastoma, p53 is predominantly found in the cytoplasm. 4- mdm2 accumulation is found in numerous cancers, such as sarcoma or breast carcinomas. 5- PTEN, a p53 regulated gene, is mutated in various types of cancer including glioblastoma. 6- Although no mutation of AKT has been found in human cancer, constitutive activation of its kinase activity has been observed via deregulation of the upstream pathway. 7- Mutations in various pathways upstream of p53 (ATM, p19ARF or Hcdk2 gene) can be observed in various types of cancer
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What does Rb do?
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Inhibits cell cycle
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Telomerase
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The reactivation of telomerase is the key to unlock human cell transformation--immortality, because it maintains chromosome length. Without it, telomeres are shortened after each cell division so after a certain number of divisions, the cell dies.
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Gleevec
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A molecular targeted therapy that inhibits BCR-Abl. It's highly selective for tumors with this translocation and has a strong selective pressure for insensitivity. Gleevec binds to BCR-Abl ATP binding site preventing it from phosphorylating
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Herceptin
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A molecular targeted therapy. It's an antibody antagonizing Her2 receptor activation in breast cancer; inhibits growth of Her2+ tumors
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Iressa
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A molecular targeted therapy. It's an EGFR antagonist, turns out it only works against very specific mutant EGFR forms
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Extrinsic factors that can be essential for cancer growth (2)
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(1) Blood supply (angiogenesis & neovascularization)
(2) Hormone signaling (androgen or estrogen dependence) |
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Angiogenesis
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Tumors secrete factors that drive formation of new blood vessels. Blocking developement of new blood vessels inhibits tumor development and spreading.
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Tomoxifen
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Drug that targets estrogen hormone dependence by blocking ligand binding
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Flutamide
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Drug that targets testosterone hormone dependence of prostate cancer by blocking cofactor interaction
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Metastasis
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Dissemination or spread of cancer cells to distance locations within the body; a hallmark of malignant disease
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Seed & Soil hypothesis
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Hypothesis that some organs are congenial for tumor cells; cancer cells metastasize in target organs due to certain genetic factors
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Dominant circulation hypothesis
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Hypothesis that cancer spreads based on circulation; cancer cells target first highly vascularized organ encountered. Lungs are a major target- one of the first highly vascularized organ encountered, but why not the heart?
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Evolution models of where cancer cells spread
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Selection of rare clones in specific organs by random acquisition of pro-metastatic mutations
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Pre-determination models of where cancer cells spread
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Poor-prognosis genes expressed in primary tumors support primary tumor and distant metastasis
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Measuring acquisition of Metastatic capability with gene expression programs
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Use microarrays to measure differences in gene expression. Upregulated combinations of genes that were upregulated in metastasis and saw this caused more metastasis.
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Cancer stem cell/tumor initiating cell
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Cells within tumor population that are transplantable and produce heterogeneous progeny. They are the drivers of metastasis and tumor recurrence.
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What type of disease is cancer?
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A cellular disorder. There are transforming viruses that carry oncogenes which are cellular in origin.
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