Carcinogenesis

Question 1

contrast direct vs. indirect acting carcinogens

Answer 1

• direct acting: weak carcinogens - dose and time dependent
• indirect acting: requires metabolic conversion – (cytochrome P450 in liver)

Question 2

what is the effect of direct acting alkylating agents?

Answer 2

cyclophosphamide –> leukemia

Question 3

what is the effect of polycyclic aromatic hydrocarbons?

Answer 3

tobacco –> lung cancer

Question 4

what is the effect of aromatic amines and azodyes?

Answer 4

hepatocellular cancer, bladder cancer

Question 5

what is the effect of nitrosamines and amides?

Answer 5

gastric cancer

Question 6

what is the effect of asbestos?

Answer 6

mesothelioma, lung cancer

Question 7

describe the mechanism of chemical carcinogenesis

Answer 7

• initiator causes mutation in the cell
• promoter causes clonal expansion
• may act at the DNA, RNA or protein level
• both agents are needed for carcinogenesis

Question 8

describe UV radiation

Answer 8

• the degrees of risk depend on:
  
  • the intensity of exposure and quantity
• mechanisms
  
  • DNA damage
  • formation of pyrimidine dimers
  • nucleotide excision repair (NER) mechanism may be overwhelmed
• e.g.: squamous cell CA, basal cell CA, melanoma

Question 9

describe ionizing radiation

Answer 9

• electromagnetic radiation (x-ray) is carcinogenic
• atomic bomb = increased leukemia
• therapeutic irradiation = thyroid cancer
• radiant energy:
  
  • DNA damage
  • alters proteins
  • inactivates enzymes
  • injures membranes
  • ionization of macromolecules and generation of free radicals

Question 10

list the DNA oncogenic viruses

Answer 10

• HPV
  
  • papilloma (skin, larynx)
  • cervical cancer
• EBV
  
  • nasopharyngeal carcinoma
  • Burkitt’s lymphoma
• HBV
  
  • hepatocellular carcinoma

Question 11

describe carcinogenesis by HPV

Answer 11

Question 12

describe how EB virus leads to development of Burkitt’s lymphoma

Answer 12

Question 13

describe the RNA oncogenic viruses

Answer 13

• RNA oncogenic viruses are retroviruses (contain reverse transcriptase)
• RNA oncogenic viruses:
  
  • acute transforming
  • slow transforming
  • human T-cell leukemia virus (HTLV-1)

Question 14

describe HTLV-1

Answer 14

• RNA virus implicated in human cancer
• associated with human T-cell leukemia/lymphoma
• viral Tax protein stimulates proliferation, enhances cell survival and interferes with cell cycle controls
• proliferation initially is polyclonal
• secondary mutations lead to the outgrowth of monoclonal leukemia

Question 15

list the important oncogenic viruses

Answer 15

• EBV = Burkitts lymphoma/nasopharyngeal cancer
• HHV-8 = Kaposi’s sarcoma
• HBV/HCV = hepatocellular cancer
• HTLV = human T cell leukemia/lymphoma
• HPV = squamous cell carcinoma of vulva, vagina, anus, cervix

Question 16

describe bacterial infections involved in carcinogenesis

Answer 16

• H. pylori infection is associated with B cell lymphoma in the mucosa associated lymphatic tissue (MALToma)

Question 17

describe driver vs. passenger mutations

Answer 17

Question 18

describe genetic changes in tumors

Answer 18

• the genetic changes in tumors may be:
  
  • small (point mutations) KRAS - colon cancer
  • large (chromosomal/karyotypic) changes
• balanced translocation
  
  • CML = t(9,22)
  • Burkitt’s lymphoma = t(8,14)
• deletion: retionblastoma –> del 13q14
• gene amplification: neuroblastoma –> NMYC

Question 19

describe proto-oncogenes vs. oncogenes

Answer 19

• proto-oncogenes: normal genes that play key roles in controlling cell proliferation and differentiation
• oncogenes: deregulated or altered proto-oncogenes that lead to development of cancer

Question 20

describe point mutations in genes leading to cancer

Answer 20

• RAS (oncogene) mutation is the most common mutation in human cancers
• also occurs in tumor suppressor gene TP53

Question 21

describe translocations leading to cancers

Answer 21

Question 22

describe gene amplification leading to cancer

Answer 22

Question 23

describe growth factor oncoproteins

Answer 23

• growth factors:
  
  • mutation of growth factor genes –> oncogenic
  • PDGF –> astrocytoma​

Question 24

describe growth factor receptor oncoproteins

Answer 24

• growth factor receptors
  
  • oncogenes may encode mutated form of receptors
  • ERBB2 (HER2/neu) –> epidermal growth factor receptor - amplification –> breast cancer/stomach cancer

Question 25

describe signal transduction protein oncoproteins

Answer 25

* oncoprotein mimics function of signal transduction proteins * ABL (tyrosine kinase) - CML t(9,22) with BCR, some ALL * RAS (GTP binding protein) - carcinomas, point mutation

Question 26

describe nuclear regulatory factor oncoproteins

Answer 26

* oncoproteins regulate nuclear transcription * CMYC - Burkitt's lymphoma, t(8,14) with IgH * NMYC - neuroblastoma (amplification)

Question 27

describe cyclin and cyclin-dependent kinases (oncoproteins)

Answer 27

* mutation dysregulate cell cycle * CCND (cyclin D1): mantle cell lymphoma (t11,14) with IgH

Question 28

describe the tumor suppressor genes

Answer 28

* inhibitors of cell proliferation: loss (mutation) causes insensitivity to growth inhibitory signals; mutation of both alleles (homozygous mutation) are necessary * **RB gene** (acts on cell cycle G1 -\> S) * hypophosphorylated RB binds to E2F (transcription factor); RB mutation frees E2F --\> proliferation * **P53**: senses DNA damage and helps repair by slowing cell cycle * P53 upregulates BAX which disrupts BCL2 * lung, colon, breast, ovary cancer

Question 29

describe apoptosis regulating genes

Answer 29

Question 30

describe mutator (caretaker) genes

Answer 30

Question 31

cancer cells express the enzyme ____ which preserves \_\_\_; doesn't shorten with each replication

Answer 31

cancer cells express the enzyme **telomerase** which preserves **telomeres**; doesn't shorten with each replication