Transcript Radiation-induced carcinogenesis

Lecture 26
Radiation-induced
carcinogenesis
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• 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
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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).
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Mechanism of
carcinogenesis
• 3-multi step hypothesis
• Oncogene/anti-oncogene
hypothesis
• Four stage hypothesis
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Radiation-Induced
Carcinogenesis
• Experiments in vivo and in vitro
utilizing chemicals and radiation
identified three distinct steps in
carcinogenesis.
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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
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Other hypothesis
(Oncogene/anti-oncogene
based)
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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
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Concept of oncogene
model
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Chromosomal changes leading to
oncogene activation in human
malignancies
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Loss of tumor suppressor gene
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Rb : Familial vs Sporadic
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Most common tumor
suppressor genes
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Process of Somatic
homozygosity
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Cooperating genes
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Four-stage hypothesis
• Chromosomal damage in normal
dividing cells
• Defect in differentiation genes
• Gene defect in hyperplastic cells
• Gene defect in cancer cells
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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.
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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.
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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.
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Colon tumor model
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• 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
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Dose-response relationship
of radiation-induced cancer
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Radiation as a carcinogen
Evidence comes from:
• Tissue culture model
• Animal model
• Human model
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Tissue culture model
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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.
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Transformation per
irradiated cell
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Enhancers
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Protectors
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Transformation incidence
of irradiated cells
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Radiation + promoter
IR+TPA
IR
C3H 10T1/2
cells
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Supression of radiationinduced transformation
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Animal Model
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Radiation-induced leukemia
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Radiation-induced tumors in
mice
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Lung cancer
Bone tumor
Breast tumor
Ovarian tumor
Uterine carcinomas
•Skin cancer
•Alimentary tract tumors
•Thyroid cancer
•Pituitary tumors
•Adrenal tumors
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Alterations in oncogenes in
radiation-induced cancer
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Human Model
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Marie Curie and Irene
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Hand of dentist
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• 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
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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.
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Leukemia
• Survivors of the A-bomb attacks on
Hiroshima and Nagasaki
• Patients
treated
with
ankylosing
spondylitis
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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
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Thyroid cancer incidence
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• 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
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Basal cell carcinoma
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Basal cell carcinoma
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Risk of cancer following
iodine-131 therapy
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• 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
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Quantitative risk estimates for
radiation-induced cancer
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Quantitative
risk estimates
for radiationinduced
cancer
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Breast cancer incidence
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Breast Cancer
• Japanese female survivors of the Abomb 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
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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
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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
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Bone sarcoma incidence
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Skin cancer
Squamous cell and basal cell carcinoma
have been most frequently observed
• Radiologist
• Dentist
• X-ray technician
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Oncogenes in human
radiation-induced tumors
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Ras point mutations were also reported in human
radiogenic tumors
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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
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p53 in human radiationinduced tumors
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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
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Calculations based on
risk estimates
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Dose and
Dose-Rate
Effectiveness
Factor
(DDREF)
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Quantitative risk estimates for a
number of specific cancer sites
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Summary of risk estimates
For the population
composed of both
sexes the ICRP
recommends
the following
figures
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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.
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