Lecture 23 - Secondary Cancers in RT patients and Heritable Effects of Radiation

ONCOL 335 - Radiobiology. University of Alberta

what are secondary malignancies?

new cancers that occur in individuals as a result of previous treatment

• not a relapse of the first cancer

what is the most common secondary cancer after radiation treatment?

skin cancers

in order to estimate the risk of secondary cancers, what is needed?

the general risk in the population due to background radiation

what does this graph tell us?

Most cancers arise later in life

- Women rises earlier, men increases later

Prostate cancer appears later in life than breast cancer

the longer the patient lives after radiation therapy …

the higher the risk of getting a secondary cancer

• the cure for the first cancer causes the second cancer

what three factors increse risk of secondary cancers

1. age

2. genetic predisposition

3. carcinogen exposure

why is it hard to estimate risk of secondary cancers from radiation therapy?

due to genetics and carcinogen exposure

what two cancers occur as a result in Rb mutation

• retinoblastoma

• osteosarcoma

what two cancers occur as a result of BRCA1 mutations

• breast cancer

• ovarian cancer

what types of secondary cancers do chemotherapies mostly lead to?

leukemias

• especially AML

what type of secondary cancers does radiation therapy mostly lead to?

solid cancers

what is relative risk

the risk comparing the number of persons in exposed population showing a late effect against the number of persons who develop the same effect in an unexposed population

how is relative risk calculated

RR = observed cases/expected cases

which two organs are most likely to gain a secondary cancer after radiation therapy to the prostate

bladder and then lung

how does the relative risk of secondary cancers increase after RT to prostate

increases over time

how does the risk for sarcomas near the treatment field increase after RT to the prostate

increases vastly over time

what is a sarcoma

A type of cancer that arises from connective tissues such as bones, fat, muscles, and cartilage.

what is a carcinoma

a type of cancer that originates in the epithelial cells, which line the surfaces of organs and structures throughout the body.

what organs show an increase in secondary cancers after radiation therapy to cervix

surprisingly, not many showed an increased risk, even close organs

what percent of the target dose is received by the contralateral breast (without cancer)

5%

where do secondary cancers occur after radiation therapy in breast cancer

on the other breast!

• not sure why

what two secondary tumors occur in children after treatment for leukemia

1. meningioma

2. glioma

what age group is most sensitive to radiation induced carcinogenesis

patients receiving radiation during puberty

• increases triple negative breast cancers in women

for most elderly patients risks of radiation are far outweighted by the risk of ….

recurrence

more than 90% of secondary cancers occurring after radiotherapy are the consequence of what?

increased life expectancy because of cure from the first cancer

secondary cancers key points

how long does it take to go from spermatogonia to spermatozoa

around 10 weeks in humans

differences in gonadal kinetics between men and women

refers to the varying rates and timelines of development and maturation of gametes, with men producing sperm continuously while women have a finite number of eggs developed over a lifetime.

what dose causes permanent sterility in men

6 Gy single dose

• 2.5-3 Gy fractionated

what dose causes permanent sterility in prepubescent females

12 Gy

what dose causes permanent sterility in premenopausal females

2 Gy

how does radiation effect hormone balance in men

no effect, doesnt change hormone balance, libido, and physical capability in men

how does radiation effect hormone balance in women

produces hormonal changes like those seen in menopause

what are heritable effects

adverse health effects due to mutations in germ cells

does radiation produce new heritable effects?

no, but it increases the indicence of the same effects that occur spontaneously

where does information on genetic effects by irradiation come from?

animal studies

what do Hermann Muller prove?

a quantitative connection between radiation and mutations on fruit flies

• observed changes in eye color, wings, lethality

what are the three categories heritable effects can be classified as

1. mendelian effects

2. chromosomal effects

3. multifactorial effects

mendelian effects

caused by mutations on single genes on the autosomes or sex chromosomes

chromosomal effects

caused by gross abnormalities in either the architecture or number of chromosomes

multifactorial effects

disease known to have a genetic component but whose transmission pattern cannot be described as mendelian

examples of mendelian effects

‘dominant, recessive, or sex-linked’ diseases

• Huntington’s disease (dominant)

• sickle cell anemia (recessive)

• hemophilia (sex-linked male)

examples of chromosomal effects

abnormal number or aberrations of chromosomes

• downsyndrome (trisomy 21)

• embryonic death

examples of multifactorial diseases

manifestation at birth or chronic disease with late onset

• cleft lip (manifestation at birth)

• diabetes

mutate vs. mutant

mutate = gained through external means, not inherent at birth

mutant = genetic mutation inherent at birth

what is the radiation doubling dose

the amount of radiaion required to produce twice as many mutations that occur spontaneously in a generation

what is the relative mutation risk

relative mutation risk per unit dose

• reciprocal of doubling dose

low relative mutation risk implies a ____ doubling dose

high

what was the megamouse project

a project used to determine mutation rates in mice under various irradiation conditions

three conclusions of megamouse project

1. Different mutations have different radiosensitivity.

2. Dose rate effect reduces mutation risk if exposure is spread out.

3. Longer gap between radiation exposure and conception reduces genetic risk.

estimated doubling dose time from A bomb survivors

1.56 Sv

what are epigenetics

gene expression with DNA sequence alterations

what is imprinting

certain genes are expressed are only expressed from one parent’s allele

• if father’s genes are imprinted, only mother’s allele is expressed

rare in mammals

diseases caused by epigenetics

• cancer

• schizophrenia

• angelman syndrome

• prader-willi syndrome