reproductive consequences of cancer treatment in childhood · 2015. 4. 26. · genetic effects in...
TRANSCRIPT
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Reproductive Consequences of Cancer Treatment
in Childhood
18 September 2012
Jeanette Falck Winther, MD, DMSc Head of Research Group
Childhood Cancer Survivorship Survivorship Unit
Danish Cancer Society Research Center Copenhagen, Denmark
Dedicated to childhood cancer survivors and their children and to all children who are fighting cancer
European Cancer Rehabilitation & Survivorship Symposium 2012
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Context
The treatment of children and young adults with cancer has been a great
success
but
There are concerns about ill effects that cancer treatment may have on
children born to cancer survivors
Radiation and many cancer drugs may produce trans-generational germ cell mutations leading to genetic
disease in the next generation
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In genetic counseling, in the area of mutagenicity of the human gonad, the ultimate concern is hereditary disease
Does cancer treatment induce damage of human germ cells?
Does it cause actual disease in the offspring,
- or mutational events of no clinical significance?
These concerns are voiced by
geneticists
pediatric oncologists
and other specialists in this field
-
- but also by the former childhood
cancer patients themselves
Will I be able to have children of my own? Will my children be healthy? Will they have birth defects or malignancies?
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Laboratory studies of germ-cell mutagenesis
Decades of experimental research have shown that both chemicals and ionizing radiation are potent germ-cell mutagens in mice
However, no environmental exposure has been proven to cause new heritable disease in human beings
”There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random de novo mutations rather than biological differences between animal and human susceptibility”
Wyrobek et al, Environ Mol Mutagen, 2007
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Genetic effects in Japanese atomic bomb survivors
55,000 children born to survivors
• Untoward pregnancy outcomes (major congenital malformations, and/or stillbirths and/or neonatal deaths)
• Cytogenetic abnormalities
• Numeric aberrations (sex-aneuploidy or Down)
• Structural abnormalities (translocations)
• Sex of child
• Childhood cancer
• Death of offspring
• Growth and development
• Protein mutations
• DNA microarray-based comparative genomic hybridization
Schull et al, J Rad Prot, 2003
Neel et al, Teratology, 1999
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Various indicators of possible genetic damage - markers of potential damage to germ cells
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Results of the first population-based studies
Cohort studies
• Pregnancy outcomes (spontaneous and induced abortions and stillbirths)
• Sex ratio
• Chromosomal abnormalities
• Congenital malformations
• Hospitalizations
Case-cohort study
• Genetic disease (including chromosomal
abnormalities, congenital
malformations, stillbirths,
and neonatal deaths)
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Pregnancies by age
Age at pregnancy
10 15 20 25 30 35 40 45 50
Nu
mb
er
of
pre
gn
an
cie
s
1
10
100
1000
10000
Population
Sisters
Survivors
Figure 2
Log-frequency distribution of 34,560 pregnancies among female cancer survivors
and sisters and population comparison women, by age at pregnancy
Winther et al, JCO, 2008
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Pregnancy outcomes after childhood cancer
Female Survivors (1,479 pregnancies)
Sisters (5,092 pregnancies)
Population comparisons
(27,989 pregnancies)
% PR (95% CI) % PR % PR (95%CI)
Livebirths 69.1 0.97 (0.94-1.01) 70.2 1 (ref.) 69.8 0.98 (0.96-1.00)
Abortions 31.8 1.06 (0.97-1.15) 30.4 1 (ref.)
30.9 1.03 (0.99-1.08)
Stillbirths 0.3 1.1 (0.4- 2.9) 0.3 1 (ref.)
0.3 1.1 (0.6-1.8)
Proportion ratios (PR) of pregnancy outcome among childhood cancer survivors and comparison groups
(sisters as referent)
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Spontaneous abortion
Risk of spontaneous abortion (PR) among childhood cancer survivors (sisters as referent)
Number of pregnancies
Number of miscarriages
PR (95% CI)
Sisters 5,092 304 1 (ref.)
Population Comparisons
27,989 1,718 0.98 (0.87-1.11)
Survivors 1,479 109 1.23 1.00-1.52
Wilms 58 10 3.0 (1.6-5.5)
Radiotherapy
No 1,006 63 1.1 (0.8-1.4)
Yes 457 44 1.6 (1.2-2.2)
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High dose irradiation to the pituitary gland and the ovary and uterus
and risk of spontaneous abortion
Ovary/uterus: low low high Pituitary gland: low high low
This slight excess risk may have resulted from uterine damage after high-dose pelvic radiation (a non-heritable somatic effect) - although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out
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First and second-trimester terminations, by indication
Survivors did not have more induced abortions - most occurring during the first trimester in all three cohorts Survivors were not more likely than comparisons to elect a second-trimester abortion because of physical or mental conditions (< 2% of all induced abortions; §2; §3.1, §3.4 and §3.6 combined) – or fetal abnormality (< 1%; §3.3)
Winther et al, JNCI, 2009
Induced abortions
Indication by section of The Danish Abortion Act
Survivors Sisters Population comparison
group
n % n % n %
Total 292 (100) 961 (100) 5 505 (100)
First-trimester termination
§1 By week 12 271 (92.8) 902 (93.9) 5 131 (93.2)
Second-trimester termination 7 (2.4) 29 (3.0) 174 (3.2)
§2 Danger to woman’s life 0 2 8
§3.1 §3.2 §3.3 §3.4 §3.5 §3.6
Deterioration of woman’s health Criminal act Abnormal fetus Physical or mental suffering Young age or immaturity Serious strain
1 0 2 2 0 2
7 0 9 0 4 7
42 2
45 2
15 55
§6 Below age 18 0 0 4
§7.1 Without Danish residence 0 0 1
Unknown 15 (5.1) 34 (3.5) 222 (4.0)
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Sex ratio in offspring
The first population-based study to investigate whether radiotherapy received by childhood cancer patients affected the sex ratio of their offspring
The sex ratio for male (0.99) and female survivors (1.00) was similar and did not differ significantly from that in the Danish population (1.06)
Radiotherapy did not influence the sex ratio of the children
No dose-related changes over categories of estimated parental radiation dose to gonads
Winther et al, Br J Cancer, 2003
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Chromosomal abnormalities in offspring
Adjusted* proportion of live-born children with abnormal karyotypes in survivor families and in the sibling families * Exclusion of hereditary cases and inclusion of prenatally
diagnosed and terminated cases (after correction for expected viability)
Winther et al, Am J Hum Genet, 2004
2,630 offspring of
4,676 survivors
5,504 offspring of 6,441 siblings
Chromosomal abnormality
5.5 (0.21%) 11.8 (0.21%)
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Congenital malformations in offspring
Adjusted prevalence proportion ratios (PPRs) and hazard ratios (HRs) of congenital malformations registered at birth and at any age, respectively, among offspring of childhood cancer survivors in comparison with offspring of siblings Malformations slightly more prevalent in offspring of survivors and in offspring of irradiated (PPR 1.2) to non-irradiated (1.0) survivors. No dose-response
Winther et al, Clin Genet, 2009
1,715 offspring of 3,963 survivors
6,009 offspring of
5,657 siblings
RR (95% CI)
Congenital malformations at birth
44 (2.6%) 140 (2.3%) 1.1 (0.8-1.5)
Congenital malformations at any age*
96 (5.6%) 301 (5.0%) 1.1 (0.9-1.4)
*median follow-up 8.2 yrs; range 0-25
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Hospitalization in offspring
Winther et al, Int J Cancer 2010
The probability for offspring of survivors of being hospitalized before a given age in childhood – overall and for selected diagnostic groups (infections and respiratory diseases shown) - was remarkably close to that in the comparison groups (siblings’ offspring and a population comparison offspring group) 6-fold excess risk in offspring of being hospitalized for cancer
Cohort Survivors offspring
pop. comparison Siblings offspring
Age
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A case-cohort study relating adverse prenancy outcomes to radiation dose to gonads
• Patterned largely on the genetic studies of
Japanese atomic bomb survivors
• Computation of the gonadal doses made it possible to interpret the epidemiological results in light of dose–response evaluations
Measurement in anthropomorphic phantoms
Winther et al, Int J Clin Oncol 2012
Phantom is set up and treated in same way as patient and radiation doses to organs are estimated
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Risk of genetic disease among of the children of cancer survivors, by radiation dose to ovary,
uterus or testes of survivor parent
Organ dose (cGy) of
survivor parent Cases Subcohort
Members Adjusted
RR 95% P-
Value
Offspring Offspring
No (%) No. (%)
Female cancer survivor
Ovarian min dose 0.96
0 (non-irradiated) 52 (69) 306 (68) 1.00 referent > 0 - 0 - 0 -
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Summary of findings (I)
• No evidence that radiotherapy or chemotherapy causes adverse pregnancy outcomes that could conceivably be related to inherited germline mutations
• No indications of an altered sex ratio among the offspring
• No increases in the risks for chromosome aberrations, congenital malformations, or hospitalizations, except for cancer in offspring due to familial cancer syndromes
• Further confirmed in the case-cohort study, in which mutagenic doses of chemotherapy and radiotherapy to the gonads were not associated with genetic defects in the children of cancer survivors
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Summary of findings (II)
• High radiation doses to the uterus in young girls, however, seemed to be linked to serious adverse pregnancy outcomes, such as spontaneous abortions and neonatal death in premature immature infants
This increased risk of fetal death in females (but not in conceptuses of males) treated
with ionizing radiation to the pelvis in infancy and childhood is probably
attributable to radiation damage to the infantile uterus, either connective tissue or
vascular supply, and not to germ line mutation
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Failure to detect human germ cell mutagenic effects…
• may be a consequence of inadequate study size, too low exposure, failure to measure the appropriate outcome
• or perhaps – the phenomenon that the mammalian organism can eliminate serious chromosome abnormalities or lethal mutations early in pregnancy and, therefore, result in surviving offspring that have a normal or background incidence of birth defects or genetic disease
Draper, Radiation Protection Dosimetry, 2008
Brent, Health Physics, 2007
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Genetic counselling
”Your child had a spontaneous change or mutation in the egg or sperm that led to her
It is nothing you did or did not do during your pregnancy or before conception
– it just happens”
This explanation is in line with the fact that
No environmental agent has been proved to cause germ cell mutations
that manifest as hereditary disease in the offspring
Mulvihill JJ, J Community Genet, 2012