Radiation-induced carcinogenesis Lecture 26 Radiation-induced carcinogenesis

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

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).

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

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

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

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

Concept of oncogene model

Chromosomal changes leading to oncogene activation in human malignancies

Loss of tumor suppressor gene

Rb : Familial vs Sporadic

Most common tumor suppressor genes

Process of Somatic homozygosity

Cooperating genes

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

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.

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.

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.

Colon tumor model

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

Dose-response relationship of radiation-induced cancer

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

Tissue culture model

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.

Transformation per irradiated cell

Enhancers

Protectors

Transformation incidence of irradiated cells

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

Supression of radiation-induced transformation

Animal Model

Radiation-induced leukemia

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

Alterations in oncogenes in radiation-induced cancer

Human Model

Marie Curie and Irene

Hand of dentist

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

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.

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

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

Thyroid cancer incidence

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

Basal cell carcinoma

Basal cell carcinoma

Risk of cancer following iodine-131 therapy

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

Quantitative risk estimates for radiation-induced cancer

Quantitative risk estimates for radiation- induced cancer

Breast cancer incidence

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

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

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

Bone sarcoma incidence

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

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

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

Calculations based on risk estimates

Dose and Dose-Rate Effectiveness Factor (DDREF)

Quantitative risk estimates for a number of specific cancer sites

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

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.