Pathoma Ch 3 Flashcards
-Two factors that can determine clonality -One form that determines clonality of B lymphocytes
- G6PD usually 1:1 for different isoforms in hyperplasia. In neoplasia, only ONE isoform is present (G6PD is on X chromosome, so inherit one from each parent normally) 2. Androgen receptor isoform (present on X chromosome, only inherit one from each parent) 3. Immunoglobulin light chain phenotype. Light chain is kappa or lambda. Normal k:l 3:1. This ratio maintained in hyperplasia (polyclonal). This ratio increases above 6:1 in lymphoma, which is monoclonal
Leading cancers by incidence and by mortality men and women
Incidence
Women/MEn
- breast/prostate
- lung
- colorectal
Mortality
Women/Men
- Lung
- breast/prostate
- colorectal
General rules about screening and cancer development and the 4 main types of screening
- Begins as SINGLE mutated cell
- Need 30 divisions before earliest sx arise
1. Pap smear: detects cervical dysplasia (CIN) before becomes carcinoma
- Mammography: detect in situ breast cancer (DCIS) before invades or invasive carcinoma before palpable
- PSA and digital exam: detect carcinoma (forms on outside of prostate)
- Hemocult fecal test and colonoscopy: detect adenoma before becomes carcinoma or before spreads
Carcinogenic Agensts cause what associated cancer
Aflatoxins
Alkylating Agents
Alcohol
Arsenic
Asbestos
Aflatoxins: Hepatocellular carcinoma. Derived from aspergillus, which can contaminate stored rice and grains
Alkylating Agents: as a side effect of chemo treatment, can develop lymphoma/leukemia down the line
Alcohol: squamous cell carcinoma of oropharynx and upper esophagus and hepatocellular carcinoma
Arsenic: squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver (present in cigarette smoke)
Asbestos: lung carcinoma MORE THAN mesothelioma
Carcinogenic Agensts cause what associated cancer
Cigarette Smoke
Nitrosamines
Naphthylamine
Vinyl Chloride
Nickel, chromium, beryllium, silica
Cigarette Smoke: carcinoma of oropharynx, esophagus, lung, kidney, bladder, pancreas. Polycyclic hydrocarbons are particularly carcinogenic
Nitrosamines: stomach carcinoma (intestinal, not diffuse), seen in smoked foods. High in Japan
Naphthylamine: Urothelial carcinoma of bladder (cigaretts)
Vinyl Chloride: angiosarcoma of liver. Found in PVC pipes
Nickel, chromium, beryllium, silica: lung carcinoma (occupational hazards)
Ongogenic Viruses
EBV
HHV-8
HBV (DNA), HCV (RNA)
HTLV-1
High Risk HPV (subtypes 16, 18, 31, 33)
EBV: nasopharyngeal carcinoma (chinese male, African), Burkitt Lymphoma, CNS lymphoma in AIDS
HHV-8: Kaposi Sarcoma (tumor of endothelial cells, seen in eastern european males, AIDS pts, transplant pts)
HBV (DNA), HCV (RNA): Hepatocellular carcinoma
HTLV-1: Adult T-cell leukemia/lymphoma
High Risk HPV (subtypes 16, 18, 31, 33): squamous cell carcinoma of vulva, vagina, anus, cervix, adenocarcinoma of cervix
Radiation causing carcinogenesis
Ionizing (nuclear reactor accidents)
Nonionizing (UVB sunlight)
Ionizing (nuclear reactor accidents): AML, CML, papillary carcinoma of thyroid (via generation of free radicals, OH-)
Nonionizing (UVB sunlight): basal cell carcinoma, squamous cell carcinoma, melanoma of skin (pyrimidine dimers that cannot be excused by restriction endonucleases)
Oncogene broad categories (5)
- Growth Factor: Platelet derived growth factor (PDGF)
- Growth Factor Receptors: HER2/neu, RET, KIT
- Signal Transducers: RAS gene family, ABL
- Nuclear Regulators: c-MYC, N-MYC, L-MYC
- Cell Cycle Regulators: Cyclin D1, CDK4
Growth Factor ongogene (1)
- PDGFB leading to astrocytoma (due to autocrine loop creating excessive PDGF)
Growth Factor Receptors oncogenes (3)
- HER2/neu: Epidermal Growth Factor receptor amplification leading to a subset of breast carcinomas (Herceptin sensitive)
- RET: neural growth factor leading to MEN2A, MEN2B, medullary carcinoma of thyroid
- KIT stem cell growth factor receptor leading to Gastrointestinal Stromal Tumor (GIST)
Signal transducers oncogenes (2)
- RAS gene family leading to GTP-ase mutation leading to overactive GTP, prolonging activating of RAS, resulting in increased growth signals. LEads to carcinomas, melanoma, lymphoma (80% of human tumors have this mutation)
- ABL is a tyrosine kinase seen in t(9:22) BCR and results in CML and some types of ALL (adult forms)
Nuclear regulator ongogenes (3)
- c-MYC is a transcription factor that involves t(8:14) involving Ig Heavy chain (14) and c-MYC (8) translocation resulting in Burkitt Lymphoma
- N-MYC –> Neuroblastoma
- L-MYC –> Lung carcinoma (small cell)
Cell cycle regulator oncogenes (2)
- Cyclin D1 drives cell through G1–>S phase of cell cycle. t(11:14) translocation with cyclin D1 (11) and Ig Heavy (14) resulting in overexpression of Cyclin D1 leading to mantle cell lymphoma
- CDK4 seen in melanoma
Two examples of tumor suppressor genes
1. p53: regulates the progression of cell cycle from
G1–>S. p53 upregulates BAX, which disrupts BCL2 (the molecule that keeps cytochrome C inside cell and keeps it from inducing apoptosis). In mutation, p53 cannot regulate cell cycle. BOTH copies of p53 must be knocked out for tumor formation (2 hit hypothesis).
2. Retinoblastoma (Rb): regulates progression from
G1–>S. Rb holds E2F transctiotion factor. Rb is phosphorylated by cyclin D1/cyclin dependent kinase (CDK4). Rb mutation results in free E2F, allowing free progression through cell cycle. BOTH copies must be knocked out for tumor formation
Li Fraumeni Syndrome
Sporatic/Germline Rb mutations
Li Fraumeni: gernline p53 mutation (2nd hit is somatic), characterized by propensity to develop multiple types of carcinomas and sarcomas
Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland).
Rb mutations:
Sporatic (both hits are somatic), characterized by unilateral retinoblastoma
Germline results in familial retinoblastoma (2nd hit is somatic). Characterized by bilateral retinoblastoma and osteosarcoma
