1. Radiation-induced carcinogenesis
Lecture 26
Radiation-induced carcinogenesis

2. Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in pre-natally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates

3. Effect of Ionizing radiation
Electromagnetic radiation (such as X- and gamma rays) are indirect ionizing radiation which deposits energy in the tissues through secondary electrons. These electrons can damage the DNA directly or can interact with water, leading to the formation of hydroxyl radicals that can interact with DNA and the enzymes. These processes will disrupt biochemical pathways and produce changes that will lead to cell death, neoplasia (in the somatic tissue), or heritable genetic damage (in the reproductive tissue).

4. Mechanism of carcinogenesis
3-multi step hypothesis
Oncogene/anti-oncogene hypothesis
Four stage hypothesis

5. Radiation-Induced Carcinogenesis
Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis.

6. 3- Steps
Initiation
Initiating events in chromosomes (such as aberrations) or in DNA. Initiators are radiation, chemical carcinogens, UV etc
Promotion
Low doses of tumor initiators are necessary to convert the initiated cells to cancer cells. Examples are TPA, phorbol esters, estrogen and excessive fat.
Progression
Increased genetic instability resulting in aggressive growth phenotype

7. Other hypothesis (Oncogene/anti-oncogene based)
Activation of proto-oncogenes
Loss of anti-oncogenes
Infection with certain viruses
Substitution of normal promoters of proto-oncogenes with strong promoters of viruses
Chromosomal aberrations

8. Concept of oncogene model

9. Chromosomal changes leading to oncogene activation in human malignancies

10. Loss of tumor suppressor gene

11. Rb : Familial vs Sporadic

12. Most common tumor suppressor genes

13. Process of Somatic homozygosity

14. Cooperating genes

15. Four-stage hypothesis
Chromosomal damage in normal dividing cells
Defect in differentiation genes
Gene defect in hyperplastic cells
Gene defect in cancer cells

16. Chromosomal damage in normal cells
Low or high dose radiation exposure can lead to chromosomal damage in normal cells. These cells may die, divide or differentiate.

17. Defect in differentiation genes
One or two normal damaged cells develop a defect in differentiation genes, which prevent them from a normal pattern of differentiation and death. Continuing division of these cells leads to hyperplasia and develop in adenoma.

18. Gene defect in hyperplastic cells
One or two hyperplastic cells in any adenoma can accumulate additional gene defects due to mutations or chromosomal damage, which can make them cancerous.

19. Colon tumor model

20. Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in pre-natally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates

21. Dose-response relationship of radiation-induced cancer

22. Radiation as a carcinogen
Evidence comes from:
Tissue culture model
Animal model
Human model

23. Tissue culture model

24. Tissue culture model
Above 100 rads: the transformation frequency may exhibit a quadratic dependence on doses.
Between 30 and 100 rads: the transformation frequency may not vary with dose
Below 30 rads: the transformation frequency may be directly proportional to dose.

25. Transformation per irradiated cell

26. Enhancers

27. Protectors

28. Transformation incidence of irradiated cells

29. Radiation + promoter
IR+TPA IR
C3H 10T1/2
cells

30. Supression of radiation-induced transformation

31. Animal Model

32. Radiation-induced leukemia

33. Radiation-induced tumors in mice
Lung cancer
Bone tumor
Breast tumor
Ovarian tumor
Uterine carcinomas
Skin cancer
Alimentary tract tumors
Thyroid cancer
Pituitary tumors
Adrenal tumors

34. Alterations in oncogenes in radiation-induced cancer

35. Human Model

36. Marie Curie and Irene

37. Hand of dentist

38. Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in pre-natally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates

39. Importance of age at exposure and time since exposure
Children and young adults are much more susceptible to
radiation-induced cancer than the middle- and old-aged.

40. Leukemia Survivors of the A-bomb attacks on Hiroshima and Nagasaki
Patients treated with ankylosing spondylitis

41. Thyroid Cancer
Survivors of the A-bomb attacks on Hiroshima and Nagasaki
Residents of the Marshall islands exposed to iodine-131
Children treated with x-rays for an enlarged thymus
Children treated for diseases of the tonsils and nasopharynx
Children epilated with x-rays for the treatment of tinea capitis

42. Thyroid cancer incidence

43. Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in pre-natally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates

44. Basal cell carcinoma

45. Basal cell carcinoma

46. Risk of cancer following iodine-131 therapy

47. Initiation, promotion, progression
Dose response for radiation-induced cancers
Importance of age at exposure and time since exposure
Malignancies in pre-natally exposed children
Second tumors in radiation therapy patients
Effects of chemotherapy on incidence
Risk estimates in humans
Calculations based on risk estimates

48. Quantitative risk estimates for
radiation-induced cancer

49. Quantitative
risk estimates
for radiation-
induced
cancer

50. Breast cancer incidence

51. Breast Cancer
Japanese female survivors of the A-bomb attacks on Hiroshima and Nagasaki
Female patients in a Nova Scotia sanatorium subjected to multiple flouroscopies during artificial pneumothorax for pulmonary tuberculosis
Females treated for postpartum mastitis and other benign conditions

52. Bone Cancer
Young persons, mostly women, employed as dial painters, who ingested radium as a result of licking their brushes into a sharp point while applying luminous paint to watches and clocks
Patients given injections of radium-224 for the treatment of tuberculosis or ankylosing spondylitis

53. Lung cancer
Persons exposed to external sources of radiation, including the Japanese survivors and those with the ankylosing spondylysis
Underground miners exposed to radon in the mine atmosphere

54. Bone sarcoma incidence

55. Skin cancer
Squamous cell and basal cell carcinoma have been most frequently observed
Radiologist
Dentist
X-ray technician

56. Oncogenes in human radiation-induced tumors
Ras point mutations were also reported in human radiogenic tumors
Other oncogenes which are of prime importance in the transformation / progression of radiogenic tumors is RET oncogene in radiation-induced thyroid tumors and c-myc gene amplification in other types of radiogenic tumors

57. p53 in human radiation-induced tumors
In humans, it has been reported that mutations in the p53 gene is a potential marker of radon-associated lung cancers from uranium miners
Higher incidence of p53 mutations were reported in thyroid carcinomas in children exposed to Chernobyl accident when compared to studies on patients who had no history of radiation exposure
On the contrary, a lower incidence of mutation (2/33) and overexpression (4/33) of p53 was reported in PTC from children exposed to radiation after Chernobyl accident

58. Calculations based on
risk estimates

59. Dose and
Dose-Rate
Effectiveness
Factor
(DDREF)

60. Quantitative risk estimates for a
number of specific cancer sites

61. Summary of risk estimates
For the population
composed of both
sexes the ICRP
recommends
the following
figures

62. Summary More than one theory on the mechanism of carcinogenesis
Evidence indicate that genes such as oncogenes and anti-oncogenes are implicated in radiogenic tumors.
Experiments from tissue culture model and also observations from humans exposed to radiation (unintentionally and accidently) strongly suggests that radiation is a potent carcinogen.
Radiation can induced malignancy such as leukemia, breast cancer, lung cancer, bone cancer etc., depending on the latent period.