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91 Cards in this Set
- Front
- Back
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What are the 4 most common
cancers of adult males? What are the 3 most common causes of cancer death in adult males? |
Incidence:
1 Prostate 2 Lung 3/4 Colon/Rectum Mortality 1 Pancreas 2 Lymphoma 3 Leukemia Path-Neo2-ppft-10 |
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What are the 4 most common
cancers of adult females? What are the 3 most common causes of cancer death in adult females? |
Incidence:
1 Lung 2 Breast 3/4 Colon/Rectum Mortality: 1 Pancrease 2 Ovary 3 Leukemia Path-Neo2-ppft-10 |
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What is the peak age for cancer incidence/death in adults?
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Incidence: 50‐85
Death females 40‐79 males 60‐79 Path-Neo2-ppt-5 |
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Epidemiology of Cancer
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2nd leading cause of death;
1/4 of all mortality 1 in 3 Americans gets cancer; 1.5 mil/year 1 in 5 Americans dies of cancer, 0.5 mil/year Path-Neo2-ppt-4 |
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Epidemiology of Childhood Cancer
Deaths Tissue Types Most Common |
Cancer may occur in all age groups; may be present at birth
1/10 of all deaths in children Most frequently in rapidly growing organs: bone, bone marrow, mesenchymal elements Most common: acute leukemia and CNS tumors (60%) Path-Neo2-ppt-6 |
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Geographic variations in cancer types
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• Japan: High stomach cancer; low colon, prostate and breast cancer
• New Zealand, Arizona: high melanoma • Subsaharan Africa: Burkitt lymphoma • Eastern Asia, Africa: Hepatocellular carcinoma high; low colon and breast cancer • Immigrants to Western countries tend to develop the same types of cancer as is prevalent in adopted country Path-Neo2-ppt-15 |
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What cancers are associated with alcohol abuse?
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Increased risk of head and neck/upper aerodigestive system cancers;
--Oropharynx --Larynx --Esophagus synergistic with tobacco Hepatocellular carcinoma secondary to cirrhosis of the liver Path-Neo2-ppt-18 |
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What cancers are associated with tobacco smoke?
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• Head and neck/upper aerodigestive tract
---Lip, mouth/oropharynx ---Larynx, lungs‐ 90% of lung cancer deaths ---Esophagus • Pancreas • Urinary tract: renal cell carcinoma, transitional cell carcinoma of the kidney, ureters and bladder • Carcinoma of the uterine cervix Path-Neo2-ppt-19 |
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What cancers are associated with
UV radiation? |
Both UV-A and UV-B implicated in skin cancer
--Squamous cell carcinoma --Basal cell carcinoma --Malignant melanoma Most at risk: Fair skin; repeated sunburn; unable to tan DNA damage and local immune suppression Path-Neo2-ppt-20 |
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Cancer from Arsenic exposure
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Lung, skin, angiosarcoma
Path-Neo2-ppt-22 |
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Cancer from Asbestos exposure
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Lung; mesothelioma
Path-Neo2-ppt-22 |
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Cancer from Benzene exposure
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Leukemia, lymphoma
Path-Neo2-ppt-22 |
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Cancer from Beryllium exposure
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Lung
Path-Neo2-ppt-22 |
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Cancer from Ethylene oxide exposure
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Leukemia
Path-Neo2-ppt-22 |
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Cancer from Naphthylamines exposure
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Bladder cancer
Path-Neo2-ppt-22 |
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Cancer from Radon exposure
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Lung
Path-Neo2-ppt-22 |
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Cancer from Vinyl Chloride exposure
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Angiosarcoma
Path-Neo2-ppt-22 |
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Occupational Risk for Lung Cancer
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Arsenic, Asbestos, Beryllium, Radon
Path-Neo2-ppt-22 |
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Occupational Risk for Skin Cancer
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Arsenic
Path-Neo2-ppt-22 |
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Occupational Risk for Angisarcoma
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Aresnic, Vincyl Chloride
Path-Neo2-ppt-22 |
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Occupational Risk for Mesothelioma
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Asbestos
Path-Neo2-ppt-22 |
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Occupational Risk for Leukemia
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Benzene, Ethylene Oxide
Path-Neo2-ppt-22 |
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Occupational Risk for Lymphoma
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Benzene
Path-Neo2-ppt-22 |
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Occupational Risk for Bladder Cancer
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Naphthylamines
Path-Neo2-ppt-22 |
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Why does chronic inflammation increases the risk for cancer?
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Cytokines simulate cell growth: increase pool of stem cells
Inflammation generates reactive oxygen species Path-Neo2-ppt-24 |
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Acquired predisposition for neoplasia
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Characterized by prolonged/increased regenerative and hyperplastic proliferations
---Endometrial hyperplasia due to estrogen ---Repair from injury (burns) ---Chronic inflammation/infection Liver Cirrhosis: hepatocellular Ca Hyperplasia‐‐>Metaplasia‐‐>Dysplasia ---e.g.Cigarette smoking on bronchial epithelium Benign tumors rarely become malignant Path-Neo2-ppt-26 |
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In What Circumstnaces do benign Tumors Become Malignant?
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Benign tumors rarely become malignant
Exceptions: --certain large and / or longstanding benign neoplasms at increased risk of malignant transformation --Adenoma‐type (adenomatous) colon polyps are colon precancer Path-Neo2-ppt-27 |
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Familial Cancers
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<1% of most cancers are related to a familial cancer gene
Inherited Predisposition (Contrast to Sporadic) Most related to enzyme, receptor polymorphisms Path-Neo2-ppt-30 |
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Sporadic Cancers
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>99% of Cancers
Due to new mutations Contrast to Familial Path-Neo2-ppt-30 |
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Genes that metabolize alcohol may be linked to
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mouth, throat cancers
Path-Neo2-ppt-31 |
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What are the characteristics of familial cancers?
What types of genes are most associated with familial cancer? |
• Familial clusters (2 or more relatives of index case)
• Tend to occur at younger age, (still peak >50) • May have multiple or bilateral cancers • AD or multifactoral due to multiple low penetrance alleles • Genes, if known, tend to be tumor suppressor genes • No “marker phenotype” (characteristic associated lesions) Familial cancers include: breast, colon, ovary, brain, malignant melanoma, endocrine, others Path-Neo2-ppt-31 |
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Knudson’s Hypothesis
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1 defective gene copy in all cells =1st hit
2nd copy lost by somatic “mutation” = 2nd hit-->malignant transformation Path-Neo2-ppt-49 |
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What is the percentage of breast cancer
that is due to an inherited cancer gene (familial cancer)? |
~ 10% of breast cancer is familial;
most common familial genes account for ~3% of breast cancer Path-Neo2-ppt-43 |
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For Breast Cancer Predisposition:
genes, gene category, inheritance, function |
BRCA‐1 and BRCA‐2
Tumor suppressors which regulate transcription for homologous recombination Breast Cancer: -younger -bilateral -males --increased risk of epithelial ovarian cancer Path-Neo2-ppt-43 |
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AD Inherited Cancer Syndromes
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Most commonly Tumor suppressors
CA occurs with Loss of Heterozygosity Tumors arise in specific sites and tissues; patients are risk for tumors of multiple organs May be associated with marker phenotype Path-Neo2-ppt-47 |
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Familial retinoblastoma
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malignant eye tumor of infants
Mutated retinoblastoma genes present all cases Familial ‐ autosomal dominant Rb gene normally present in all cells in the body Path-Neo2-ppt-49 |
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Inherited cancer syndromes with marker
phenotype |
Familial adenomatous polyps of the colon
---develop multiple adenomas of colon; Multiple endocrine neoplasia (MEN) 2B ---Marfanoid habitus w/ ganglioneuromas of tongue, RET gene Neurofibromatosis types 1 and 2 Path-Neo2-ppt-57 |
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Multiple Endocrine Neoplasia 2B
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---Marfanoid habitus w/ ganglioneuromas of tongue, RET gene
Path-Neo2-ppt-49 |
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Neurofibromatosis
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Inherited defect of tumor suppressor gene, common
Syndrome of neurofibromatosis 1, NF‐1 gene ---Multiple benign neurofibromas, -----each at risk for transformation‐‐> neurofibrosarcoma ---Cafe au lait spots ---Lisch nodules, 22% of pop by age 5, 100% by age 20 -------hamartomas of melanocytes in the irises Path-Neo2-ppt-59 |
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Autosomal recessive cancer syndromes of
defective DNA repair |
Recessive inheritance ‐ rare
2 mutated alleles results in marked increased risk of cancer • Xeroderma pigmentosum • Ataxia telangiectasia • Bloom syndrome • Fanconi’s anemia Path-Neo2-ppt-65 |
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Xeroderma pigmentosum
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Autosomal recessive cancer
NER (nucleotide excision repair) gene: UVB forms pyrimidine dimers of DNA; Extreme photosensitivity to UV light 2000x increased risk of skin cancer Skin cancers occur in childhood Path-Neo2-ppt-66 |
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Ataxia telangiectasia
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Autosomal recessive
ATM (ataxia telangiectasia mutated) gene binds to damaged DNA; phosphorylates TP53 ATM gene results in chromosome fragility Manifests as --Cerebellar ataxia ---oculocutaneous telangiectasias (dilated blood vessels) ---IgA deficiency; recurrent infections Sensitive to ionizing radiation; develop leukemia; lymphoma with exposure Path-Neo2-ppt-70 |
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Bloom syndrome
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Autosomal recessive cancer from defective DNA repair
{Low Priority:] • Homozygous for BLM gene mutations • Cutaneous manifestations • Immunodeficiency • Sensitivity to UV radiation • Risk for leukemia/lymphoma Path-Neo2-ppt-73 |
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Fanconi’s anemia
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Autosomal recessive cancer from defective DNA repair
{Low Priority:] • Physical abnormalities • Pancytopenia (blood cell types: RBCs, platelets and neutrophils all reduced) • Chromosome fragility • Risk for leukemia, squamous cell carcinoma and hepatoma Path-Neo2-ppt-49 |
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Three classes of carcinogenic agents
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‐ Chemicals
‐ Radiant energy : UV and ionizing ‐ Microbial agents Path-Neo2-ppt-77 |
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Initiation
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Rapid, irreversible effect: permanent DNA damage
Insufficient alone for tumor formation Path-Neo2-ppt-83 |
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Promotion
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Induce sustained cell proliferation in initiated (mutated) cells (not intrinsically tumorigenic)
• Promoters may be exogenous chemical or physical agent: phenols, drugs endogenous mechanism ---hormones acting on breast; prostate ---bile acids in colon ---cytokines stimulating growth • Promotion confers an increased risk of additional mutations Effects reversible Path-Neo2-ppt-88 |
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Tumorogenesis from Initiation and Promotion
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image
Path-Neo2-ppt-83 |
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Direct Acting Initiators
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Require no chemical transformation
Alkylating agents, cancer chemotherapy cyclophosphamide, cisplatin; busulfan ‐‐risk for developing hematologic malignancies subsequent to therapy Highly reactive electrophilic: covalent bonds to DNA Path-Neo2-ppt-85 |
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Indirect Acting Initiators
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Procarcinogens are metabolized to carcinogens by P‐450 enzymes
Electrophilic, form adducts Classes --Polycyclic, aromatic hydrocarbons --Aromatic amines, amides and azo dyes --Nitrosamines --Natural plant and microbial products Path-Neo2-ppt-85 |
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Molecular targets of chemical carcinogens
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Distinctive :signature" pattern of DNA damage with each chemical
eg: p53 mutation of benzyopyrene (tobacco smoke) Path-Neo2-ppt-86 |
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Polycyclic Aromatic Hydrocarbons
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• Sources: product of combustion of organic material or of chemical synthesis
• Cancer site related to route of administration • Example, formation of epoxides: Benzo(a)pyrene in tobacco smoke may be related to lung cancer (unproven) Vinyl chloride: plastic manufacture; related to angiosarcoma of the liver Path-Neo2-ppt-92 |
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Nitrosamines
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• Potent carcinogens in lab animals; unproven in humans
• Implicated in: ‐ GI malignancies; sources nitrites in meat ‐ Urinary tract malignancies in smokers ‐ Esophageal carcinoma in China Path-Neo2-ppt-93 |
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Aflatoxin B1
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Potent Naturally Occurring Carcinogen
‐ Potent, indirect acting product of Aspergillus flavus fungus ‐ Hepatocellular carcinoma ‐ p53 signature mutation Path-Neo2-ppt-94 |
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Betel nuts
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Naturally Occurring Carcinogen
oral and urinary cancers Path-Neo2-ppt-83 |
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Actions of Tobacco; Alcohol
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• Cigarette smoking is
---an initiator : benzo(a)pyrene and nitrosamines ---promoter : multiple irritants • Smoking is a multiplier /co‐carcinogen for asbestos, radon gas • Alcohol is likely a promoter Path-Neo2-ppt-95 |
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HTLV‐1
Type of Virus Tissue Tropism Malignancy Mechanism |
• RNA, retrovirus
• Produces Tax gene product • Polyclonal expansion of CD4 T Cells via Tax: ----Genetic Instability and Mutation accumulation • T‐cell leukemia/lymphoma in 4% with 40+ year latency Path-Neo2-ppt-99 |
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DNA cancer‐causing viruses
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• Human papilloma virus, HPV
• Epstein Barr virus, EBV • Hepatitis B virus • Human herpesvirus, HH8 (Kaposi sarcoma virus) Path-Neo2-ppt-95 |
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What neoplasms are related to HPV infection?
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Verruca Vulgaris -warts predominantly on hands/feet
Condyloma Accuminatum: Venereal Warts Sqamous Papillomas of Mouth, Conjunctiva, Respiratory Tract Path-Neo2-ppt-110 |
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What are the features and actions of “high
risk” (carcinoma‐associated) HPV? |
‐ Viral genome integrated into nuclear DNA
‐ site is random‐ no association with a proto‐oncogene ‐ insertion is clonal ‐ E2 viral repressor is lost ‐ Repressor loss promotes over-expression of E6, E7 Path-Neo2-ppt-114 |
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Locations of cancers due to HPV
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Locations of cancers due to HPV
--vulva, vagina, cervix, penis, perianal‐‐ virtually all cases --minority of respiratory tract carcinomas: sinuses, oral cavity, lung --20% of oropharyngeal cancer Path-Neo2-ppt-113 |
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E6 & E& proteins of HPV
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• E6 protein inactivates p53 product, degrades BAX; activates telomerase
• E7 protein binds to RB (cell cycle inhibitor) Path-Neo2-ppt-117 |
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Viral oncogenesis due to HPV
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• Familial predispositon for HPV‐related cancers associated with p53 protein
polymorphisms • Interaction with environment is required for carcinogenesis, eg cancer of the cervix: ‐ cigarette smoking ‐ other STD's Path-Neo2-ppt-118 |
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List the malignancies associated with Epstein
Barr virus infection. |
• Burkitt’s lymphoma (African)
• B‐cell lymphoma ‐ immunosuppressed ---Cyclosporine suppression for cardiac transplantation • Hodgkin disease / Hodgkin lymphoma • Nasopharyngeal carcinoma [& less importantl: • Some gastric carcinomas • NK/T cell lymphoma ‐ subtype] Path-Neo2-ppt-120 |
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Name factors responsible
EBV's for oncogenic effects. |
• LMP‐1 (latent membrane protein)
‐ activates NF‐kB and JAK/STAT pathways ‐ acts as CD40 receptor for T cell signaling ‐ activates BCL2 • EBNA‐2 mimics Notch receptor; activates cyclin D and other oncogenes • vIL 10, major transforming gene prevents activation of cytotoxic T cells Path-Neo2-ppt-121 |
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EBV oncogenesis‐Burkitt’s
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• B lymphocytes infected; proliferate
• Additional stimulation to proliferate by ?co‐infection by malaria ‐‐>polyclonal expansion • Proliferating cells undergo 14-->8 chromosomal translocation • Additional mutations accumulate, including loss of immunogenicity • Viral genome present in almost all cases in Africa Path-Neo2-ppt-124 |
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Viral Oncogenesis‐EBV
Nasopharyngeal carcinoma |
• Endemic in Southern China, Eskimos, parts of Africa
• EBV viral genome present in tumor; serology elevated before onset of disease • Neoplastic cells are monoclonal squamous cells Path-Neo2-ppt-126 |
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Viral Oncogenesis
Hepatitis B and C |
• Associated with hepatocellular carcinoma
• Hepatitis C due to RNA virus • Hepatitis B due to DNA virus • Infections produce chronic viral hepatitis that persists for years • Immune response leads to growth/anti-apoptotic cytokines --->genetic accidents arise in the regenerating cells Path-Neo2-ppt-131 |
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Hepatocellular carcinoma in
Hepatitis B |
• Multifactoral oncogenic effect
---Ongoing hepatocyte regeneration ---Environmental agents, eg. aflatoxins from Aspergillus flavus implicated as cofactor • Hepatitis B is endemic in Asia and Africa with high rate of hepatocellular carcinoma Path-Neo2-ppt-132 |
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How do two viruses work synergistically to
cause Kaposi sarcoma? |
Path-Neo2-ppt-132
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Human Herpes Virus 8 or KS
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• DNA virus
• Associated with Kaposi sarcoma in HIV positive and HIV negative individuals • KS is a neoplastic proliferation of blood vessels or vessel‐forming mesenchyme • Rare prior to 1980 Path-Neo2-ppt-134 |
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Kaposi Sarcoma in HIV
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• Most common neoplasm in males with HIV; an AIDS defining lesion
• Usually involves the skin, may involve any visceral organ • Aggressive; may metastasize • Red to red‐purple (violaceous) patches, plaques or nodules • Primitive mesenchyme or endothelial cells infected by KS virus • Cytokines and tat gene product from HIV infected CD4 T lymphs induce KS –infected cell proliferation Path-Neo2-ppt-134 |
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What malignancy/malignancies are associated
with Helicobactor pylori infection? |
• Chronic gastritis and ulceration
• 3% of infected persons: 2 most common types of gastric cancers ---Adenocarcinoma of the stomach ---Gastric lymphoma of mucosa‐associated lymphoid tissue (MALT) Path-Neo2-ppt-141 |
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CagA
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cytotoxin‐associated A gene ‐mimics growth g factor initiating signaling
CagA containing strains of H pylori most assoc. with adenocarcinoma Path-Neo2-ppt-144 |
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Chronic infection of H pylori in predisposed host produces
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polyclonal then monoclonal B lymphocyte proliferation (MALT lymphoma)
‐ regresses with antibiotic therapy Path-Neo2-ppt-144 |
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Diagnosis of cancer requires:
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‐ biopsy with histopathologic diagnosis
‐ cytology (slides) Path-Neo2-ppt-146 |
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Effects of Tumors on the Host
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• Cachexia (wasting)
• Local effects: impingement on adjacent structures • Metastases with distant regional effects • Functional activity such as hormone synthesis • Paraneoplastic syndromes Path-Neo2-ppt-148 |
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Cancer Cachexia
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• Wasting syndrome: loss of body fat and lean body mass with profound weakness, anorexia and anemia.
• Occurs in 50% of cancer patients, especially GI, pancreatic, lung cancers • Leads to death in 30% ‐ atrophy of diaphragm; other respiratory muscles • Tumor secretions: ---PIF (proteolysis inducing factor) ---LMF (lipid mobilizing factor): increases fatty acid oxidation and pro‐inflammatory cytokines • Pro‐inflammatory cytokines also induce by host immune response ---TNF‐a; IL‐1, IFN‐gamma --> acute phase reactions Degradation of Myosin and Dystrophin via proteosome Path-Neo2-ppt-149 |
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Paraneoplastic Tumors
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Hormone elaboration by nonendocrine tumors
Path-Neo2-ppt-157 |
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Paraneoplastic syndromes
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Effects remote from a tumor not explained by elaboration of hormones indigenous to tumor
• Occur in 10% of patients with malignancy ---May precede detectable tumor allowing for early diagnosis ---May be lethal ---May mimic metastatic disease Two types: --Endocrinopathies‐ elaboration of hormone‐like substances egs on 161 --Syndromes due to antibodies myopathies, myasthenias Path-Neo2-ppt-159 |
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Lambert‐Eaton Syndrome
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Antibody mediated progressive muscle weakness associated with lung cancer
an examples of a paraneoplastic syndrome Path-Neo2-ppt-162 |
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Paraneoplastic Acanthosis nigricans
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• Gray‐black pigment with keratosis of skin in intertrigenous (skin fold) areas
• May be associated with visceral malignancy ‐ especially gastric carcinoma ‐ also lung and breast cancer Path-Neo2-ppt-163 |
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Hematologic Syndromes
Associated with Malignancy |
• Hypercoagulable states: Trousseau syndrome; venous thrombosis, chronic DIC, NBTE
• Paraneoplastic granulocytosis due to secretion of CSF by tumor • Thrombocytosis (30% of cancer patients) - tumor production of thrombopoietin or IL‐6 [• Skin lesions : multiple types; most related to autoimmunity • GI syndromes • Hypoalbuminemia • Nephrotic syndrome • Others] Path-Neo2-ppt-166 |
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Serum Tumor Markers
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Biochemical indicators of the presence of a tumor
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-169 |
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CEA
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Serum Tumor Marker for colon cancer
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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Alpha‐fetoprotein
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Serum Tumor Marker for liver and testicular cancer
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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Beta‐HCG
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Serum Tumor Marker for choriocarcinoma ‐ malignancy derived from placenta or germ cells (ovary; testis tumors)
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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PSA
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Serum Tumor Marker for prostate ca
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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VMA; HVA, NSE
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Serum Tumor Marker forneuroblastoma
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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CA‐15‐3
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Serum Tumor Marker for breast cancer
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
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CA‐ 125
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Serum Tumor Marker for ovarian cancer
Not Diagnostic, Used to screen/identify patients for additional testing Path-Neo2-ppt-170 |
