Pathology: Neoplasia - Etiology and Carcinogenesis
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- What is a DIRECT-ACTING CARCINOGEN?
- does not to need to be chemically altered to act (usually weak carcinogens)
- What is an INDIRECT-ACTING CARCINOGEN?
- needs metabolic conversion from PROCARCINOGEN to ULTIMATE CARCINOGEN
- What are the 2 stages of chemical carcinogenesis?
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1. initiation (carcinogenic agent irreversibly damages DNA (is mutagenic))
2. promotion (acts (reversibly) to stimulate cell proliferation and enhance carcinogenic process, but not carcinogenic in itself) - How does UV radiation cause cancer? What is the extreme disease example of this process?
- induces thymine dimers; XERODERMA PIGMENTOSUM (failure of DNA excision repair mechanisms)
- What gene does v-sis mimic?
- gene for beta chain of PDGF
- What the 4 classes of regulatory genes are the principal targets of genetic damage?
- proto-oncogenes, cancer suppressor genes, genes that regulate apoptosis, DNA repair genes
- How do oncoproteins differ from the protein products of proto-oncogenes?
- oncoproteins are devoid of important regulatory elements, their production is not dependent on growth factors or external signals
- What are some examples of cancers that result from ionizing radiation?
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-skin cancer/myeloid leukemias in radiologists
-lung cancer in uranium miners
-thyroid cancer in pts w/head/neck radiation therapy
-acute and chronic myeloid leukemias in atomic blast survivors
-osteosarcoma in radium watch-dial workers - What are the 3 oncogenic DNA viruses?
- HPV (human papillomavirus), HBV (hep B), EBV (epstein-barr)
- What is the general carcinogenic mechanism of DNA viruses?
- integrate viral DNA into host genomes, resulting in host expression of viral mRNA coding for specific proteins
- What are the major types of neoplasms implicated by HPV?
- genital tract neoplasms, esp. premalignant lesions and cancers of cervix (sexually transmitted); laryngeal papillomas; benign squamous papillomas (warts)
- What major types of neoplasms are implicated by EBV?
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-Burkitt's lymphoma = tumor of B lymphocytes (stimulates prolif of B cells, inc opportunity for translocation and oncogene activation)
-nasopharyngeal cancer - What major types of neoplasms are implicated by HBV?
- hepatocellular carcinoma
- What is the general carcinogenic mechanism of retroviruses?
- transcription of viral genomic RNA into DNA by viral reverse transcriptase (can encode for a viral oncogene itself, or encode for a promoter sequence that is inserted near a protooncogene)
- What is the only known oncogenic retrovirus? What type of neoplasm does it cause?
- human t-cell leukemia virus type I (HTLV-1); t cell leukemia/lymphoma
- What are the general downstream effect of ras?
- activates regulators of proliferation, including kinases, which flood nucleus w/signals for cell prolif
- What protein mediates the "on-off" activity of ras, by making sure ras turns off shortly after activation?
- GAP (GTPase-activating protein) -- hydrolyzes ras-GTP to ras-GDP
- What is the resulting defect when there is a mutation of the ras gene?
- mutant ras proteins bind GAP but fail to be inactivated, thus signal is always on
- What is the single most common oncogene abnormality in human tumors?
- mutation of ras gene (25-30%)
- What are some examples of oncogenes that regulate transcription of DNA in the nucleus?
- myc, fos, myb
- How does pRB regulate the cell cycle?
- guardian of G1->S checkpoint; CDKs (activated by cyclin) phosphorylate pRB which allows entry of cells in to S phase
- What is an example of oncogene activation by point mutation?
- ras
- What is insertional mutagenesis?
- insertion of retroviral promoter or enhancer sequence into host genome that leads to inc expression of nearby oncogene
- What is the translocation that occurs in Burkitt's lymphoma?
- 8:14; c-myc proto-oncogene is translocated adjacent to Ig heavy chain (region w/hectic transcriptional activity), and inc expression of c-myc
- What is the translocation that occurs in chronic myeloid leukemia (CML)?
- 9:22; c-abl protooncogene is translocated adjacent to bcr locus; the c-abl-bcr hybrid (on the "Philadelphia chromosome") encodes for a protein with inc tyrosine kinase activity
- What is the translocation in acute promyelocytic leukemia?
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15:17; results in fusion of retinoic acid receptor (RAR-alpha) and transcriptional unit PM
*can induce remission w/all-trans retinoic acid (vit A analogue)* - What do "double-minutes" and "homogenous staining regions" on chromosomes indicate?
- extensive gene amplification
- What are 2 types of neoplasms which involve amplification, and what genes are amplified?
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neuroblastoma (N-myc) -> correlates strongly w/disease progression
breast cancers (c-erbB2) -> associated w/poor prognosis - What is the two-hit hypothesis of Knudson?
- 2 mutations are required to express neoplastic phenotype (both alleles must be inactivated)
- What is the prototypic cancer suppressor gene for which the two-hit hypothesis applies?
- Rb gene--inactivation causes retinoblastoma (childhood tumor)
- How is the cell cycle affected if the Rb gene is inactivated?
- normally, cell cycle can only move to S phase if pRb is phosphorylated, setting free transcription factors. if pRb is absent, "molecular breaks" of cell cycle are gone, cells proceed easily into S phase
- What is the most common target for genetic alteration in human tumors?
- p53
- What is the normal function of p53?
- causes cell cycle arrest in G1 when there is DNA damage, so it can be repaired. if damage is not repaired, p53 induces apoptosis
- What syndrome results from familial loss of p53, and what is this syndrome characterized by?
- Li-Fraumeni syndrome; wide variety of tumors (breast, soft tissue carcinomas, brain tumors, leukemias, etc)
- What are some major cancer suppressor genes?
- Rb, p53, WT-1, BCRA-1, APC, NF-1
- What syndrome results from deletion or inactivation of WT-1?
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Wilms tumor (most common renal neoplasm in children)
(WT-1 = Wilms Tumor-1) - What types of neoplasms result from inactivation of APC?
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familial polyposis coli and adenocarcinoma of colon
(APC = adenomatous polyposis coli) - What types of neoplasms result from inactivation from BRCA-1?
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familial propensity to breast and ovarian cancers
(BRCA-1 = BReast CAncer-1) - What are some common genes associated with apoptosis?
- bcl-2, bax, p53 (by increasing transcription of bax)
- What is the molecular defect in hereditary nonpolyposis colon carcinoma (HNPCC or Lynch syndrome)?
- mutation in DNA mismatch repair genes
- What is the genetic defect in von Recklinghausen neurofibromatosis type 1?
- mutations in NF-1 tumor suppressor gene (which fns as a GAP protein that inactivates ras)
- What is the genetic defect in multiple endocrine neoplasia type IIa?
- mutations in ret protooncogene transmitted in germline