Pathology (neoplasm 6)

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  1. How does amplification present in molecular studies?
    • Two mutually exclusive patterns are seen: multiple small, centric structures called double minutes and homogeneous staining regions.
    • The latter derive from the insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved genes; because regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a G-banded karyotype 
  2. The most interesting cases of amplification involve ...... in neuroblastoma and breast cancers
    N-MYC/ ERBB2
  3. In neuroblastomas with N-MYC amplification, the gene is present as......................
    both double minutes and homogeneous staining regions.
  4. Amplification of ............................. correlates with disease progression in small-cell cancer of the lung
    C-MYC, L-MYC, or N-MYC
  5. ......amplification is associated with poor prognosis in neuroblastoma
  6. What are the most important translocations?
    • ABL (9q)–BCR (22) (9;22): CML
    • ATF1 (12)–EWS (22) (12;22): Malignant melanoma of soft parts
    • BCL1 (11)–IgH (14) (11;14): Mantle cell lymphoma
    • BCL2 (18)–IgH (14) (14;18): Follicular lymphoma
    • FLI1 (11)–EWS (22) (11;22): Ewing's sarcoma
    • LCK (1)–TCRB (7) (1;7): T cell ALL
    • MYC (8q)–IgH (14q) (8;14): Burkitt's lymphoma, B cell acute lymphocytic leukemia
    • PAX3 (2)–FKHR/ALV (13) (2;13): Alveolar rhabdomyosarcoma
    • PAX7 (1)–KHR/ALV(13) (1;13): Alveolar rhabdomyosarcoma
    • RET (10)–PKAR1A (17) (10;17): Thyroid carcinoma
    • TAL1(1)–TCTA (3) (1;3): Acute T cell leukemia
    • TRK (1) TPM3 (1) Inv1(q23;q31): Colon carcinoma
    • WT1 (11)–EWS (22) (11;22): Desmoplastic small round cell tumor
    • HOX (11)-TCRA(14) (10;14): T cell ALL
    • TMPRSS2 (21q) with other genes (ERG or ETV1) -->(21:21)(21:17)(21:7) Prostatic adenocarcinoma
    • PML(15q) RARA(17q) t(15q:17q) AML M3
  7. What are epigenetic changes?
    • Epigenetics refers to reversible, heritable changes in gene expression that occur without mutation.
    • Such changes involve post-translational modifications of histones and DNA methylation, both of which affect gene expression.
    • In normal, differentiated cells, the majority of the genome is not expressed. Some portions of the genome are silenced by DNA methylation and histone modifications that lead to the compaction of DNA into heterochromatin
  8. What are the characteristic epigenetic changes observed in cancer?
    global DNA hypomethylation and selective promoter-localized hypermethylation
  9. What are some important genes that are hypermethylated in cancers?
    • All are tumor suppressors
    • CDKN2A, a complex locus that encodes two tumor suppressors, p14/ARF and p16/INK4a from two different reading frames; p14/ARF is epigenetically silenced in colon and gastric cancers, while p16/INK4a is silenced in a wide variety of cancers.
    • BRCA1 in breast cancer
    • VHL in renal cell carcinomas
    • MLH1 mismatch-repair gene in colorectal cancer
  10. What is the relation of genomic imprinting to tumors?
    demethylation of an imprinted gene leading to its biallelic expression (loss of imprinting)—can also occur in tumor cells
  11. What are the changes of chromatin in cancers?
    • 1) The current paradigm is that there is a histone code in which various modifications to the tails of histones, such as acetylation and methylation, lead to activation or repression of transcription.
    • 2) EZH2 (overexpressed in breast and prostate) is the enzymatic component of the multiprotein polycomb repressive complex 2, which places repressive chromatin marks at the promoter of genes. overexpression of EZH2 leads to the repression of tumor suppressors, such as p21.
    • 3) There is significant cross-talk between the chromatin-remodeling enzymes and the DNA-methylation machinery. For example, the placement of repressive chromatin marks by enzymes like EZH2 in cancer cells results in the recruitment of DNA methylases, methylation of promoters, and durable repression of gene expression.
  12. What are the general features of miRNA?
    • miRNAs are small noncoding, single-stranded RNAs, approximately 22 nucleotides in length, that are incorporated into the RNA-induced silencing complex.
    • The miRNAs mediate sequence-specific recognition of mRNAs and, through the action of the RNA-induced silencing complex, mediate post-transcriptional gene silencing.
    • Given that miRNAs control cell growth, differentiation, and cell survival, it is not surprising that they play a role in carcinogenesis
  13. How can miRNA participate in neoplastic transformation?
    • either by increasing the expression of oncogenes or by reducing the expression of tumor suppressor genes
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  14. ...........oncogene induces cells to secrete growth factors and permits them to grow without anchorage to a normal substrate (anchorage independence), whereas the ..... oncogene renders cells more sensitive to growth factors and immortalizes cells
    RAS /MYC
  15. What is the multi-step carcinogenesis regarding CRC?
    • Many of these cancers are believed to evolve through a series of morphologically identifiable stages: colon epithelial hyperplasia followed by formation of adenomas that progressively enlarge and ultimately undergo malignant transformation.
    • Inactivation of the APC tumor suppressor gene occurs first, followed by activation of RAS and, ultimately, loss of a tumor suppressor gene on 18q and loss of p53.
    • Also depicted is the senescence pathway if p53 loss does not occur
    • Indeed, it has been shown that most cells in most adenomas are senescent.
    • It is thought that mutation of a proto-oncogene such as RAS drives a cell into senescence instead of proliferation by activating the DNA-damage checkpoint.
    • The loss of p53 in adenomas prevents oncogene-induced senescence, allowing the adenomatous cells to continue to proliferate, generating a carcinoma.
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  16. ..........mutation is an early event and loss of .............occurs late in the process of tumorigenesis of CRC
    APC /P53
  17. ......mutation can induce senescence in CRC
  18. What are the two groups of direct acting carcinogens?
    • Alkylating Agents: β-Propiolactone  Dimethyl sulfate  Diepoxybutane  Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas)
    • Acylating Agents:  1-Acetyl-imidazole  Dimethylcarbamyl chloride
    • Polycyclic and Heterocyclic Aromatic Hydrocarbons : Benz[a]anthracene , Benzo[a]pyrene, Dibenz[a,h]anthracene, 3-Methylcholanthrene, 7,12-Dimethylbenz[a]anthracene
    • Aromatic Amines, Amides, Azo Dyes:  2-Naphthylamine (β-naphthylamine) , Benzidine, 2-Acetylaminofluorene, Dimethylaminoazobenzene (butter yellow)
    • Natural Plant and Microbial Products: Aflatoxin B1 , Griseofulvin , Cycasin , Safrole, Betel nuts
    • Others:  Nitrosamine and amides  Vinyl chloride, nickel, chromium, Insecticides, fungicides, Polychlorinated biphenyls
  20. Diepoxybutane is an.................carcinogen
  21. What are two steps in the carcinogenesis?
  22. What are the concepts in initiation promotion sequence?
    • Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator); an initiated cell is altered, making it potentially capable of giving rise to a tumor (groups 2 and 3). Initiation alone, however, is not sufficient for tumor formation (group 1).  
    • Initiation causes permanent DNA damage (mutations). It is therefore rapid and irreversible and has “memory.” This is illustrated by group 3, in which tumors were produced even if the application of the promoting agent was delayed for several months after a single application of the initiator.  
    • Promoters can induce tumors in initiated cells, but they are nontumorigenic by themselves (group 5). Furthermore, tumors do not result when the promoting agent is applied before, rather than after, the initiating agent (group 4). This indicates that, in contrast to the effects of initiators, the cellular changes resulting from the application of promoters do not affect DNA directly and are reversible. Promoters enhance the proliferation of initiated cells, an effect that may contribute to the development of additional mutations in these cells. That the effects of promoters are reversible is further documented in group 6, in which tumors failed to develop in initiated cells if the time between multiple applications of the promoter was sufficiently extended
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  23. What are the effects of initiation?
    • Results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator);
    • an initiated cell is altered, making it potentially capable of giving rise to a tumor. 
    • Initiation alone, is not sufficient for tumor formation
    • Initiation causes permanent DNA damage (mutations).
    • It is therefore rapid and irreversible and has “memory.”
    • Tumors are produced even if the application of the promoting agent was delayed for several months after a single application of the initiator
  24. What are the features of promotion?
    • Promoters can induce tumors in initiated cells, but they are nontumorigenic by themselves.
    • Furthermore, tumors do not result when the promoting agent is applied before, rather than after, the initiating agent.
    • This indicates that, in contrast to the effects of initiators, the cellular changes resulting from the application of promoters do not affect DNA directly and are reversible.
    • Promoters enhance the proliferation of initiated cells, an effect that may contribute to the development of additional mutations in these cells.
    • That the effects of promoters are reversible is further shown by that tumors failed to develop in initiated cells if the time between multiple applications of the promoter was sufficiently extended
  25. What is the characterisitc chemical features of initiator carcinogens?
    • All initiating chemical carcinogens are highly reactive electrophiles (have electron-deficient atoms) that can react with nucleophilic (electron-rich) sites in the cell.
    • Their targets are DNA, RNA, and proteins, and in some cases these interactions cause cell death
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  26. What is the hallmark of damage caused by initiators?
    Nonlethal irreversible damage to DNA, that can be passed to daughter cells
  27. What are the category of initiators?
    direct acting and indirect acting
  28. What are the features of direct-acting initiators?
    • Direct-acting agents require no metabolic conversion to become carcinogenic.
    • Most of them are weak carcinogens but are important because some are cancer chemotherapeutic drugs (e.g., alkylating agents)
    • Secondary form of cancer is usually acute myeloid leukemia.
    • The risk of induced cancer is low, but its existence dictates judicious use of such agents
  29. What is the mc cancer induced by alkylating agents?
  30. What are indirect acting agents?
    chemicals that require metabolic conversion to an ultimate carcinogen before they become active
  31. What are the examples of indirect acting agents?
    • polycyclic hydrocarbons—are present in fossil fuels.
    • benzo[a]pyrene is formed in the high-temperature combustion of tobacco in cigarette smoking (cause of lung cancer)
    • Polycyclic hydrocarbons are also present in smoked meats and fish.
    • The aromatic amines and azo dyes are another class of indirect-acting carcinogens that were widely used in the past in the aniline dye and rubber industries
  32. The principal active products in many hydrocarbons are .............
  33. What is the major mechanism of carcinogenesis in hydrocarbons?
    The principal active products in many hydrocarbons are epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins.
  34. What are the determinants of carcinogenic potency?
    • inherent reactivity of its electrophilic derivative
    • balance between metabolic activation and inactivation reactions
  35. Most of the known carcinogens are metabolized by ........................................................
    cytochrome P-450–dependent mono-oxygenases
  36. Polymorphisms in which enzymes can regulate susceptibility to carcinogenesis?
  37. What is an example of CYTP450 polymorphism in cancer?
    • The metabolism of polycyclic aromatic hydrocarbons, such as benzo[a]pyrene by the product of the P-450 gene, CYP1A1
    • Approximately 10% of the white population has a highly inducible form of this enzyme that is associated with an increased risk of lung cancer in smokers
  38. the primary target for chemical carcinogens
  39. What is the role of aflatoxin B1 in carcinogenesis?
    • Produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts.
    • There is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in parts of Africa and the Far East. Interestingly, aflatoxin B1 produces mutations in the p53 gene; 90% or more of these mutations are a characteristic G : C➙T : A transversion in codon 249 (called 249(ser) p53 mutation). 
    • By contrast,p53 mutations are much less frequent in liver tumors from areas where aflatoxin contamination of food is not a risk factor, and the 249(ser) mutation is uncommon.
    • Thus, the detection of the “signature mutation” within the p53 gene establishes aflatoxin as the causative agent.
  40. What are the seuence of Initiation and Promotion of Chemical Carcinogenesis?
    • Unrepaired alterations in the DNA are essential first steps in the process of initiation
    • For the change to be heritable, the damaged DNA template must be replicated.
    • Thus, for initiation to occur, carcinogen-altered cells must undergo at least one cycle of proliferation so that the change in DNA becomes fixed.
    • In the liver, many chemicals are activated to reactive electrophiles, yet most of them do not produce cancers unless the liver cells proliferate within a few days of the formation of DNA adducts.
    • In tissues that are normally quiescent, the mitogenic stimulus may be provided by the carcinogen itself, because many cells die as a result of toxic effects of the carcinogenic chemical, thereby stimulating regeneration in the surviving cells.
    • Alternatively, cell proliferation may be induced by concurrent exposure to biologic agents such as viruses and parasites, dietary factors, or hormonal influences.
    • Agents that do not cause mutation but instead stimulate the division of mutated cells are known as promoters
    • The carcinogenicity of some initiators is augmented by subsequent administration of promoters (such as phorbol esters, hormones, phenols, and drugs) that by themselves are nontumorigenic.
    • Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells. Such cells have reduced growth factor requirements and may also be less responsive to growth-inhibitory signals in their extracellular milieu.
    • Driven to proliferate, the initiated clone of cells suffers additional mutations, developing eventually into a malignant tumor.
    • Thus, the process of tumor promotion includes multiple steps: proliferation of preneoplastic cells, malignant conversion, and eventually tumor progression, which depends on changes in tumor cells and the tumor stroma—the process of multistep carcinogenesis
  41. For the change induced by initiator to be heritable, .....................................
    the damaged DNA template must be replicated
  42. What are promoters?
    Agents that do not cause mutation but instead stimulate the division of mutated cells are known as promoters
  43. What are the multiple steps of tumor promotion?
    proliferation of preneoplastic cells, malignant conversion, and eventually tumor progression
  44. What are some hereditary cancers?
    • 1q: HPC1:prostate
    • 2p:MSH2:HNPCC
    • 3p:MLH1:HNPCC
    • 3p: VHL: Kidney, cerebellum, pheochromocytoma
    • 5q:APC: CRC, Intestinal adenoma
    • 7q: MET: Hereditary papillary renal carcinoma
    • 9p: p16INK4: Melanoma, pancreatic 
    • 9q: TSC1: Angiofibroma, renal angiomyolipoma
    • 9q: PTCH: Gorlin: Basal cell carcinoma, medulloblastoma, jaw cysts
    • 10q: RET: Medullary thyroid carcinoma, pheochromocytoma
    • 10q:PTEN: Breast, thyroid
    • 11q:MEN1: Parathyroid, endocrine, pancreas, and pituitary
    • 11P: WT1: Wilms
    • 11q:ATM: Breast
    • 13q:BRCA2: Breast, ovarian
    • 13q: RB1: Retinoblastoma, osteosarcoma
    • 15q:BLM: bloom
    • 16q:CDH1: hereditary diffuse gastric
    • 16P: TSC2: Angiofibroma, renal angiomyolipoma
    • 17p:P53: Sarcoma, breast
    • 17q:BRCA1: Breast, Ovary
    • 17q:NF1: Neurofibroma, neurofibrosarcoma, brain
    • 18q: SMAD4: juvenile polyposis
    • 22q: NF2: Vestibular schwannoma, meningioma, spine
  45. UV rays derived from the sun cause an increased incidence of ..............................................
    squamous cell carcinoma, basal cell carcinoma, and possibly melanoma of the skin
  46. How is UV related to skin cancers?
    • Nonmelanoma skin cancers are associated with total cumulative exposure to UV radiation
    • Melanomas are associated with intense intermittent exposure—as occurs with sunbathing
  47. Which UV portion is most likely to be responsible for skin cancers?
    • Three types of UV exists: UVA (320–400 nm), UVB (280–320 nm), and UVC (200–280 nm).
    • Of these, UVB is believed to be responsible for the induction of cutaneous cancers.
    • UVC, although a potent mutagen, is not considered significant because it is filtered out by the ozone shield around the earth (hence the concern about ozone depletion)
  48. The carcinogenicity of UVB light is attributed to its formation of ...................................
    pyrimidine dimers in DNA
  49. pyrimidine dimers are repaired by the ...........................................................
    nucleotide excision repair pathway
  50. What happens to DNA in excessive sun exposure?
    It is postulated that with excessive sun exposure, the capacity of the nucleotide excision repair pathway is overwhelmed, and error-prone nontemplated DNA-repair mechanisms become operative that provide for the survival of the cell at the cost of genomic mutations that in some instances, lead to cancer
  51. What are ionizing radiations?
    Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) radiations
  52. True or False: ionizing radiation of all type is carcinogenic
  53. Most frequent cancers associated with ionizing radiation are .................................
    the acute and chronic myeloid leukemia
  54. What are the associated cancers in ionizing radiation?
    • Most frequent are the acute and chronic myeloid leukemia.
    • Cancer of the thyroid follows closely but only in the young.
    • In the intermediate category are cancers of the breast, lungs, and salivary glands
  55. Which tissues are resistant to carcinogenic effect of ionizing radiation?
    skin, bone, and the GI tract
  56. HTLV-1 causes a form of T-cell leukemia/lymphoma that is endemic in certain parts of .....................
    Japan and the Caribbean basin
  57. HTLV-1 has tropism for ...................
    CD4+ T cells
  58. True or False: HTLV-1 does not contain an oncogene, and no consistent integration next to a proto-oncogene has been discovered
  59. What is true about the viral integration by HTLV1?
    although the site of viral integration in host chromosomes is random (the viral DNA is found at different locations in different cancers), the site of integration is identical within all cells of a given cancer (clonal)
  60. What is the function of Tax in HTLV1?
    • The product of this gene is essential for viral replication, because it stimulates transcription of viral mRNA by acting on the 5′ long terminal repeat.
    • Tax protein can also activate the transcription of several host cell genes involved in proliferation and differentiation of T cells.
    • These include the immediate early gene FOS, genes encoding IL-2 and its receptor, and GMCSF.
    • In addition, Tax protein inactivates the cell cycle inhibitor p16/INK4a and enhances cyclin D activation, thus dysregulating the cell cycle.
    • Tax also activates NF-κb, a transcription factor that regulates a host of genes, including pro-survival/anti-apoptotic genes. Another mechanism by which Tax may contribute to malignant transformation is through genomic instability. Recent data show that Tax interferes with DNA-repair functions and inhibits ATM-mediated cell cycle checkpoints activated by DNA damage
  61. What is the mechanism of T cell leukemia by HTLV1?
    • Infection by HTLV-1 causes the expansion of a nonmalignant polyclonal cell population through stimulatory effects of Tax on cell proliferation.
    • The proliferating T cells are at increased risk of mutations and genomic instability induced by Tax.
    • This instability allows the accumulation of mutations and chromosomal abnormalities, and eventually a monoclonal neoplastic T-cell population emerges.
    • The malignant cells replicate independently of IL-2 and contain molecular and chromosomal abnormalities
  62. What are the oncogenic viruses?
    • HPV
    • EBV
    • HBV
    • HHV 8
    • polyomavirus (Merkel)
  63. In ........... the HPV genome is maintained in a nonintegrated episomal form, while in ............the HPV genome is integrated into the host genome
    benign warts/cancers
  64. True or False: Integration of viral DNA is important for malignant transformation
  65. True or False: In HPV induced tumors the site of viral integration in host chromosomes is random, but the pattern of integration is clonal
  66. What is integration required for carcinogenesis of HPV?
    integration interrupts the viral DNA within the E1/E2 open reading frame, leading to loss of the E2 viral repressor and overexpression of the oncoproteins E6 and E7.
  67. What is the function of E7 of HPV?
    • The E7 protein binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle.
    • E7 protein from high-risk HPV types has a higher affinity for RB than does E7 from low-risk HPV types.
    • E7 also inactivates the CDKIs p21 and p27.
    • E7 proteins from high-risk HPV types (types 16, 18, and 31) also bind and presumably activate cyclins E and A.
  68. What is the function of E6?
    • It binds to and mediates the degradation of p53 and BAX, a pro-apoptotic member of the BCL2 family, and it activates telomerase.
    • Like E7, E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types.
    • Human p53 is polymorphic at amino acid 72, encoding either a proline or arginine residue at that position. The p53 Arg72 variant is much more susceptible to degradation by E6. Not surprisingly, infected individuals with the Arg72 polymorphism are more likely to develop cervical carcinomas
  69. What is the mechanism of cervical cancer?
    • High-risk HPV types express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis, and combat cellular senescence.
    • However, infection with HPV itself is not sufficient for carcinogenesis. For example, when human keratinocytes are transfected with DNA from HPV types 16, 18, or 31 in vitro, they are immortalized but do not form tumors in experimental animals
    • Co-transfection with a mutated RAS gene results in full malignant transformation. In addition to such genetic co-factors, HPV in all likelihood also acts in concert with environmental factors. These include cigarette smoking, coexisting microbial infections, dietary deficiencies, and hormonal changes, all of which have been implicated in the pathogenesis of cervical cancers.
    • A high proportion of women infected with HPV clear the infection by immunological mechanisms
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  70. True or False: infection with HPV itself is not sufficient for carcinogenesis
  71. What are the cancers associated with EBV?
    • the African form of Burkitt lymphoma;
    • B-cell lymphomas in immunosuppressed individuals (particularly in those with HIV infection or undergoing immunosuppressive therapy after organ transplantation);
    • a subset of Hodgkin lymphoma; nasopharyngeal and some gastric carcinomas
  72. What are the molecular basis of EBV induced cancer?
    • LMP-1 (oncogene) behaves like a constitutively active CD40 receptor, a key recipient of helper T-cell signals that stimulate B-cell growth. LMP-1 activates the NF-κB and JAK/STAT signaling pathways and promotes B-cell survival and proliferation, all of which occur autonomously. Concurrently, LMP-1 prevents apoptosis by activating BCL2.
    • EBNA-2, encodes a nuclear protein that mimics a constitutively active Notch receptor. EBNA-2 transactivates several host genes, including cyclin D and the src family of proto-oncogenes. In addition, the EBV genome contains a viral cytokine, vIL-10, that was hijacked from the host genome. This viral cytokine can prevent macrophages and monocytes from activating T cells and is required for EBV-dependent transformation of B cells.
    • In immunologically normal individuals EBV-driven polyclonal B-cell proliferation in vivo is readily controlled, and the individual either remains asymptomatic or develops a self-limited episode of infectious mononucleosis. Evasion of the immune system seems to be a key step in EBV-related oncogenesis
  73. What are the features of B cell infection with EBV?
    The infection of B cells is latent; that is, there is no viral replication and the cells are not killed, but the B cells latently infected with EBV are immortalized and acquire the ability to propagate indefinitely in vitro
  74. What are the epidemiological relations between Burkitt lymphoma and EBV infection?
    • More than 90% of African tumors carry the EBV genome.  
    • One hundred percent of the patients have elevated antibody titers against viral capsid antigens.  
    • Serum antibody titers against viral capsid antigens are correlated with the risk of developing the tumor
  75. Which observations suggest that additional factors might be involved in EBV induced Burkitt lymphoma?
    • (1) EBV infection is not limited to the geographic locales where Burkitt lymphoma is found, but it is a ubiquitous virus that asymptomatically infects almost all humans worldwide.
    • (2) The EBV genome is found in only 15% to 20% of sufferers of Burkitt lymphoma outside Africa.
    • (3) There are significant differences in the patterns of viral gene expression in EBV-transformed (but not tumorigenic) B-cell lines and Burkitt lymphoma cells. Most notably, Burkitt lymphoma cells do not express LMP-1, EBNA2, and other EBV proteins that drive B-cell growth and immortalization.
  76. How does EBV contribute to the genesis of endemic Burkitt lymphoma?
    • In regions of the world where Burkitt lymphoma is endemic, concomitant infections such as malaria impair immune competence, allowing sustained B-cell proliferation.
    • Eventually, however, T-cell immunity directed against EBV antigens such as EBNA2 and LMP-1 eliminates most of the EBV-infected B cells, but a small number of cells downregulate expression of these immunogenic antigens. These cells persist indefinitely, even in the face of normal immunity.
    • Lymphoma cells may emerge from this population only with the acquisition of specific mutations, most notably translocations that activate the c-MYC oncogene.
    • In nonendemic areas 80% of tumors do not harbor the EBV genome, but all tumors possess the t(8;14) or other translocations that dysregulate c-MYC.
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  77. True or False: in the case of Burkitt lymphoma, EBV is directly oncogenic
  78. True or False: In the case of Burkitt lymphoma,EBV by acting as a polyclonal B-cell mitogen, sets the stage for the acquisition of the t(8;14) translocation and other mutations
  79. What is the role of EBV in B-cell lymphomas in immunosuppressed patients?
    • The role played by EBV is more direct in B-cell lymphomas in immunosuppressed patients.
    • Some persons with AIDS and those who receive long-term immunosuppressive therapy for preventing allograft rejection present with multifocal B-cell tumors within lymphoid tissue or in the central nervous system. These tumors are polyclonal at the outset but can develop into monoclonal neoplasms. In contrast to Burkitt lymphoma, the tumors in immunosuppressed patients uniformly express LMP-1 and EBNA2, that are recognized by cytotoxic T cells.
    • These potentially lethal proliferations can be subdued if the immunological status of the host improves, as may occur with withdrawal of immunosuppressive drugs in transplant recipients
  80. True or False: 100% of nasopharyngeal carcinomas obtained from all parts of the world contain EBV DNA
  81. What is the possible mechanism of nasopharyngeal carcinoma caused by EBV?
    LMP-1 is expressed in epithelial cells as well. In these cells, as in B cells, LMP-1 activates the NF-κB pathway. Furthermore, LMP-1 induces the expression of pro-angiogenic factors such as VEGF, FGF-2, MMP9, and COX2, which may contribute to oncogenesis.
  82. Highest relation of EBV is to .....subtype of HL
    Lymphocyte depleted
  83. What are the HL subtypes associated with EBV infection?
    • Lymphocye depleted (100%)>MC(70%)>LR(40%)
    • Lymphocyte predominant and NS-->none
  84. What is the mechanism of EBV-associated HL?
    • Activation of the transcription factor NF-κB is a common event in classical HL.
    • NF-κB is activated either by EBV infection or by some other mechanism and turns on genes that promote lymphocyte survival and proliferation.
    • EBV+ tumor cells express latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that transmits signals that up-regulate NF-κB. Activation of NF-κB also occurs in EBV- tumors, in some instances as a result of acquired mutations in IκB, a negative regulator of NF-κB.
    • It is hypothesized that activation of NF-κB by EBV or other mechanisms rescues “crippled” germinal-center B cells that cannot express Igs from apoptosis, setting the stage for the acquisition of other unknown mutations that collaborate to produce ReedSternberg cells.
    • EBV-encoded proteins may play a part in the remarkable metamorphosis of B cells into Reed-Sternberg cells
  85. Extranodal NK/T-Cell Lymphoma is highly associated with..................
  86. What are the AML subtypes with genetic aberrations?
    • AML with t(8;21);CBFα/ETO fusion gene--> Favorable--> M2: Full range of myelocytic maturation; Auer rods easily found; abnormal cytoplasmic granules
    • AML with inv(16);CBFβ/MYH11 fusion gene--> Favorable--> M4eo: Myelocytic and monocytic differentiation; abnormal eosinophilic precursors with abnormal basophilic granules
    • AML with t(15;17); RARα/PML fusion gene--> Intermediate: M3, M3v: Numerous Auer rods, often in bundles within individual progranulocytes; primary granules usually very prominent (M3 subtype), but inconspicuous in microgranular variant (M3v); high incidence of DIC
    • AML with t(11q23;v); diverse MLL fusion genes--> Poor--> M4, M5: Usually some degree of monocytic differentiation
  87. What are the common tk mutations in MPD?
    • CML-->BCR-ABL--> Constitutive ABL kinase activation
    • PV,ET,PMF-->JAK2 point muations-> Constitutive JAK2 kinase activation
    • Systemic mastocytosis--> c-KIT point mutations--> Constitutive c-KIT kinase activation
    • ET, PMF-->MPL in 5%
  88. What are the most important genetic changes in leukemias and lymphomas?
    • B-ALL-->  t(12;21) involving CBFα and ETV6 present in 25%
    • T-ALL--> NOTCH1 mutations (50% to 70%)
    • Burkitt lymphoma-->Translocations involving c-MYC and lg loci, usually t(8;14); subset EBV-associated
    • Diffuse large B-cell lymphoma-->mc BCL2/BCL6
    • Extranodal marginal zone lymphoma--> t(11;18), t(1;14), and t(14;18) creating MALT1-IAP2,BCL10-IgH, and MALT1-IgH fusion genes
    • Follicular lymphoma--> t(14;18) creating BCL2-IgH fusion
    • Mantle cell lymphoma--> t(11;14) creating CyclinD1-IgH
    • SLL/CLL--> Trisomy 12, deletions of 11q, 13q, and 17p
  89. True or False: The HBV and HCV genomes do not encode any viral oncoproteins
  90. True or False: the HBV DNA is integrated within the human genome
  91. the dominant oncogenic effect of HBV and HCV seems to be .....................................
    immunologically mediated chronic inflammation with hepatocyte death leading to regeneration and genomic damage
  92. What are the molecular mechanisms of HBV induced carcinogenesis?
    • One key molecular step seems to be activation of the NF-κB pathway in hepatocytes in response to mediators derived from the activated immune cells.
    • Activation of the NF-κB pathway within hepatocytes blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations. Although this seems to be the dominant mechanism in the pathogenesis of viral-induced hepatocellular carcinoma, both HBV and HCV also contain proteins within their genomes that may more directly promote the development of cancer.
    • The HBV genome contains a gene known as HBx that can directly or indirectly activate a variety of transcription factors and several signal transduction pathways.
    • In addition, viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes
  93. What are the associated cancers of H.Pylori?
    gastric adenocarcinomas and gastric lymphomas
  94. What is the mechanism of HP induced gastric adenocarcinoma?
    • It involves increased epithelial cell proliferation in a background of chronic inflammation.
    • As in viral hepatitis, the inflammatory milieu contains numerous genotoxic agents, such as reactive oxygen species. There is an initial development of chronic gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer.
    • This sequence takes decades to complete and occurs in only 3% of infected patients. Like HBV and HCV, the H. pylori genome also contains genes directly implicated in oncogenesis.
    • Strains associated with gastric adenocarcinoma have been shown to contain a “pathogenicity island” that contains cytotoxin-associated A (CagA) gene. Although H. pylori is noninvasive, CagA penetrates into gastric epithelial cells, where it has a variety of effects, including the initiation of a signaling cascade that mimics unregulated growth factor stimulation
  95. What is the mechanism of MALToma by HP?
    • involve strain-specific H. pylori factors, as well as host genetic factors, such as polymorphisms in the promoters of inflammatory cytokines such as IL-1β and tumor necrosis factor (TNF).
    • It is thought that H. pylori infection leads to the appearance of H. pylori–reactive T cells, which in turn stimulate a polyclonal B-cell proliferation. In chronic infections, currently unknown mutations may be acquired that give individual cells a growth advantage.
    • These cells grow out into a monoclonal “MALToma” that nevertheless remains dependent on T-cell stimulation of B-cell pathways that activate the transcription factor NF-κB.
    • At this stage, eradication of H. pylori by antibiotic therapy “cures” the lymphoma by removing the antigenic stimulus for T cells.
    • At later stages, however, additional mutations may be acquired, such as an (11;18) translocation, that cause NF-κB to be activated constitutively. At this point, the MALToma no longer requires the antigenic stimulus of the bacterium for growth and survival and develops the capacity to spread beyond the stomach to other tissues
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Pathology (neoplasm 6)
2013-10-17 14:13:09
Pathology neoplasm

Pathology (neoplasm 6)
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