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111 Cards in this Set
- Front
- Back
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How do cells become independent of paracrine/endocrine growth signals?
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THey acquire the ability to synthesize those growth factors and an autocrine loop is created (ie, PDGF, TGF-a)
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T/F Genes for growth factors are always mutated in cancers
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False, the growth factor genes are usually not mutated, they are just over-expressed due to other oncogenes (ie RAS)
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T/F Growth factor receptors contribute to cancer only due to mutations in their gene sequences
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False, it is due to mutated receptors as well as over-expression of normal receptors (which is more common ie EGFR)
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What is over-expressed in 80% of SCC of the lung?
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EGF receptor
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What is over-expressed in 25-30% of breast cancer, adenocarcinoma of the lung, and salivary gland cancers?
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ERBB2 (HER2
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What antibody therapy can be used to treat breast cancer?
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anti-HER2 antibody administration to block the extracellular domain and impede activation
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What are the two most important signaling proteins that can contribute to cancer?
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RAS, which is associated with the membrane, and ABL which is not membrane bound
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What is the most common oncogene in human tumors?
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Mutated RAS gene, its found in about 30% of all human tumors
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What does RAS protein normally do?
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It normally binds GDP when quiescent and becomes activated when it binds GTP. In cancer it can't hydrolyze GTP so RAS stays active.
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What does active RAS do?
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It activates downstream cascades, cuh as RAF-MAP kinase which then flood the nucleus w/signals for proliferation.
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What are GAP's?
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GTPase-activating proteins that enhance the GTPase activity of RAS so that it hydrolyzes GTP and becomes inactive.
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What type of drugs can be used to treat mutated RAS?
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Drugs that block the farnesyl moiety of RAS from binding to the cell membrane. This eliminates the action of RAS
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What is the most common type of mutation of RAS gene?
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Point mutations around 12, 13, and 61 (area of binding pocket of GTP)
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How does ABL protooncogene contribute to cancer?
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ABL gene gets translocated and coupled with BCR. This causes potent tyrosine kinase activity that will lead to leukemias. Also, now ABL can't localize in the nucleus to promote apoptosis like it normally would.
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What is the most common mutation in nuclear transcription factors?
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Mutated MYC gene
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What is the function of the MYC gene?
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Normally it binds to DNA to induce transcription of cyclins that regulate cell cycle. When mutated the levels of MYC protein stay high all the time and the cell proliferates uncontrolled.
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How do cyclins work to regulate the cell cycle?
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They bind to cyclin-dependent kinases (CDK's) and phosphorylate Rb protein (cell moves from G1 to S)
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What are CDK inhibitors and how do they work?
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They inhibit CDK/cyclin complex from phosphorylating their target proteins. They are p15, p16, p18, p19, etc.
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What is the first extremely important checkpoint in cell cycle clock?
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G1 --> S. This is regulated by D cyclins and CDK4/6. They phosphorylate Rb and cell enters into S phase
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T/F Mutations that dysregulate activity of cyclins and CDK's would favor cell proliferation
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True
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Which cyclins and CDK's are most commonly involved in neoplastic transformation?
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Over-expression of cyclin D and CDK4
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What is the first and best known cancer suppressor gene?
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Rb gene
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How do familial and sporadic cases of retinoblastoma differ?
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Sporadic cases require 2 somatic mutations and familial inherit one mutation and acquire one somatic mutation.
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T/F Sporadic and familial retinoblastomas have different end results
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False, both end up with two mutated copies of Rb gene and get same cancer
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T/ F Loss of the normal Rb genes is only found in retinoblastomas
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False, it occurs in breast, lung, and bladder cancers as well.
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T/F Cells only require one mutant copy (heterozygote) of the Rb gene to induce neoplasm
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False, both Rb genes (homozygote) must be mutated, thus it is a recessive cancer gene.
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What type of gene acts in the growth-inhibitory pathway?
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Tumor suppressor genes
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What are the two mechanisms of antigrowth signals?
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Cause cells to remian in G0 and cause cells to lose replicative potential
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Which checkpoint of the cell cycle do antigrowth signals work on?
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G1 --> S checkpoint
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Does phosphorylation activate or inactivate Rb protein?
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It inactivates it and the cell is allowed to proceed from G1 to S phase. When active (dephosphorylated) it acts as a brake on the cell cycle
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What is the most common CDK inhibitor to become mutated and contribute to neoplastic transformation?
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CDKN2A, also called INK4a and p16
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Which is more significant, germ line derived mutations in INK4a or somatically acquired mutation?
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Somatically acquired mutations are much more commonly found in cancers.
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What are the 4 most commonly mutated regulatory genes found in cancers?
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INK4a, cyclin D, CDK4, and Rb. All of these lead to disruption of Rb function
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What viral products bind to hypophosphorylated Rb?
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SV40 and polyomavirus large T antigen, adenoviruses EIA protein, and HPV E7 protein
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What is the best known antiproliferative signal?
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TGF-b
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How does TGF-b work to inhibit cell proliferation?
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It binds to three types of receptors and arrests the cells in G1 phase by regulating Rb pathways
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What are the mechanisms of TGF-b?
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Stimulated production of CDK inhibitors and inhibits transcription of CDK's and cyclins. Both result in decreased phosphorylation of Rb
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What are the most common mutations in the TGF-b pathway?
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type 2 TGF-b receptor and SMAD protein mutations.
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T/F At least one component of TGF-b pathway is mutated in 100% of pancreatic cancers and 83% of colon cancers
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True
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What does TP53 do?
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It can't really be classified into any one category, it directs the cell to the appropriate response, either cell cycle arrest or apoptosis
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What stresses can trigger TP53 response?
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Anoxia, inappropriate oncogene expression, and damage to DNA
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What is the function of MDM2 protein?
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It binds to TP53 when cell isn't stressed and decreases its half-life. When cell is stressed, it releases TP53.
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What are the two main categories of genes induced by TP53?
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Genes that cause cell cycle arrest and those that cause apoptosis
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T/F DNA viruses can subvert two of the best-understood tumor suppressor genes, Rb and TP53
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True
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What is the most important gene that provides protection from apoptosis for tumor cells?
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BCL2. This usually becomes defective via a translocation (14;18) of BCL2 next to a very active gene and it gets over-expressed.
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What cancers are commonly caused by over-expression of BCL2?
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Slow growing lymphomas that result from lack of B cell death, not from explosive growth
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Why are normal human cells limited to 60-70 rounds of replication?
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It is due to the progressive shortening of the telomeres with each division.
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How do tumor cells avoid normal cellular senescence?
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By activating telomerase to maintain normal telomere length
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T/F Telomerase is only active in 10% of cancers
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False, it is active in 85-95% of cancers
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What is the size limit of a tumor without angiogenesis?
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1-2 mm, the max distance oxygen and nutrients can diffuse from blood vessels
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Which important angiogenic factors are made by tumor cells?
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VEGF and FGF
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What is thrombosponsin-1?
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It is an antiangiogenic molecule induced by TP53. With loss of TP53 angiogenesis will proceed
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What are the two phases of the metastatic cascade?
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Invasion of ECM and vascular dissemination
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How do E-cadherins contribute to progression of cancer?
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They normally act as intercellular glue holding cells together, but when function is lost via mutation this allows tumor cells to detach and metastasize
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How would a protease inhibitor work against cancer?
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It would inhibit the proteases that degrade the ECM and allow metastases
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How do tumor cells in the blood stream protect themselves from antitumor host cells?
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By aggregating and adhereing to circulating leukocytes, particularly platelets.
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T/F Precise localization of metastases can be predicted in most forms of cancer
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False, there is no way to know for sure
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What are the two phases of the metastatic cascade?
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Invasion of ECM and vascular dissemination
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How do E-cadherins contribute to progression of cancer?
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They normally act as intercellular glue holding cells together, but when function is lost via mutation this allows tumor cells to detach and metastasize
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How would a protease inhibitor work against cancer?
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It would inhibit the proteases that degrade the ECM and allow metastases
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How do tumor cells in the blood stream protect themselves from antitumor host cells?
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By aggregating and adhereing to circulating leukocytes, particularly platelets.
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T/F Precise localization of metastases can be predicted in most forms of cancer
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False, there is no way to know for sure
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What directs the homing of tumor cells in circulation to a metastatic site?
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This is called organ tropism and is directed by expression of adhesion molecules whose ligand is expressed in certain organs, and chemokines also play a role.
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What causes xeroderma pigmentosum?
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It is caused by a mutation in proteins responsible for DNA repair. UV light damages DNA and these pts cant repair the damage so they get cancer easily
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What type of cancers are implicated in BRCA1 gene mutations?
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Epithelial ovarian cancers in women and prostate cancer in men
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What type of cancers are implicated in BRCA2 gene mutations?
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Breast cancer in men and women
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What type of genes are BRCA1/2?
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Tumor suppressor genes that interact with DNA repair proteins. They are recessive genes, so both copies must be mutated
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What are three common autosomal recessive disorders that are associated with high risk for cancer?
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Bloom syndrome, ataxia telangiectasia, and Falconi anemia
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T/F All tumors follow basically the same sequence in obtaining metastatic changes
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False, they happen at differing time intervals and in different orders...but they have to all happen for a malignant cancer to develop.
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How is tumor progression defined?
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Over time a tumor may exhibit accelerated growth and invasiveness and have greater ability to form distant metastases
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T/F As a tumor becomes more aggressive and less differentiated, it will be less susceptible to anti-cancer agents
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False, it will be more susceptible
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What does tumor heterogeneity refer to?
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The fact that mutations accumulate in tumor clone cells independently and sub-clones are then produced
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Describe evolution of tumors
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Mutations create sub-clone populations in a tumor, some are less adept at survival and some more. So the tumor tends to become composed of the more aggressive sub-clones that can survive host defenses.
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T/F Generally cancers develop pools of aggressive sub-clones at about the same rate
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False, all cancers differ in how fast this process happens
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What is Philadelphia chromosome (Ph)?
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It is a translocation between chromosomes 22 and 9. Most commonly found in chronic myelogenous leukemia (CML)
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Which chromosomal translocations are common in Burkitt's lymphoma?
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Chromosomes 8 and 14
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What are the most common chromosomal structural abnormalities in tumor cells?
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Translocations are the most common and deletions are the second most common
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T/F Chromosomal deletions are more commonly found in hematopoietic tumors (leukemias/lymphomas)
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False, they are more common in non-hematopoietic solid tumors
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Which genes are most commonly involved in gene amplifications?
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N-MYC and HER-2 genes
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What are the 3 classes of carcinogenic agents?
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Chemicals, radiant energy, and microbial agents
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What are direct acting carcinogens?
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They require no chemical transformation to induce carcinogenicity
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What are indirect acting carcinogens?
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They only become active after metabolic conversion and are generally referred to as procarcinogens/ultimate carcinogens.
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Why do carcinogens typically react with RNA, DNA, and cellular proteins?
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Because carcinogens are electrophiles (electron deficient) and those molecules are electron rich.
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What is a promoter?
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It is an augmenting agent not carcinogenic by itself. Some carcinogens need promoter and some don't
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T/F In general direct acting carcinogens are weak and are often used in chemotherapeutic drugs
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True, many of them are alkylating agents so they work to treat some cancers
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Which carcinogen is thought to be produced endogenously in the stomach?
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Nitrosamines due to amines reacting with nitrites added to certain foods or derived from bacterial action
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What is aflotoxin-B1?
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It is produced by the fungus Aspergillus that grow on improperly stored grains. It is correlated with hepatocellular carcinoma
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T/F In general direct acting carcinogens are weak and are often used in chemotherapeutic drugs
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True, many of them are alkylating agents so they work to treat some cancers
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Which carcinogen is thought to be produced endogenously in the stomach?
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Nitrosamines due to amines reacting with nitrites added to certain foods or derived from bacterial action
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What is aflotoxin-B1?
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It is produced by the fungus Aspergillus that grow on improperly stored grains. It is correlated with hepatocellular carcinoma
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Which gene mutation is associated with aflatoxin B1?
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Characteristic mutation of TP53
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How can promoters cause tumorigenesis if they're not mutagenic themselves?
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Because the effects of promoters are pleiotropic
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What is TPA and how does it work?
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It is the best studied promoter. Works by activating protein kinase C and also increases growth factor secretion
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What drug is used to combat breast cancer?
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Tamoxifen. It is an estrogen receptor antagonist that blocks proliferative effects of estrogen on breast tumor
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What type of mutation is most common in radiation carcinogenesis?
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Double stranded DNA breaks
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Why is the latent period of irradiation cancers so long?
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Because it takes time for other necessary mutations to accumulate in the progeny cells.
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What structures do UV rays damage?
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UVA is long wave length and damages underlying dermis. UVB is short wave length and damages epidermis or mucosal epithelium.
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What type of sun exposure causes melanomas?
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Intense intermittent exposures, like tanning or sunbathing.
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What type of sun exposure causes non-melanoma skin cancers?
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Lots of cumulative total exposure to UV
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What type of mutation typically happens from UV exposure?
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Mutations in TP53 gene
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What is the only known human retrovirus associated with cancer?
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HTLV-1
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What is the function of TAX gene in HTLV-1 induced cancers?
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It activates transcription of IL-2 and its receptor as well as GM-CSF. This leads to T-cell proliferation and eventually leukemia
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What are the 4 main oncogenic DNA viruses?
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HPV, EBV, KSHV (HHV-8), HBV
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T/F 50% of oropharyngeal cancers are HPV associated
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False, about 20% are HPV associated
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T/F HPV 16 and 18 DNA are found in 75-100% of cervical SSC
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True
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What type of cancers are associated with EBV?
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Mostly B-cell lymphomas, but also nasopharyngeal carcinoma, T-cell lymphoma, and rare NK cell lymphoma
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T/F In Burkitt lymphoma, B cells don't express viral antigens on the cell surface
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True, for this reason it goes undetected by the host immune system.
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Which gene is commonly mutated in B cells infected with EBV?
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MYC oncogene usually translocated to chromosome 14 from 8
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T/F B lymphoblast proliferations in EBV infected AIDS/transplant patients don't express viral antigens on their surfaces
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False, they do so they can be neutralized by the immune system if function is restored
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Which viral DNA can be found in 90% of liver cancer pts infected with this virus
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Hep B virus
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What is the pathogenesis of liver cancer in pts infected with HBV?
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Viral integration leads to chromosome rearrangements and multiple deletions of tumor suppressor genes
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