S T U D Y P R O T O C O L Open Access
Genetic variation in gonadal impairment in
female survivors of childhood cancer: a
PanCareLIFE study protocol
Anne-Lotte L. F. van der Kooi
, Eva Clemens
, Linda Broer
, Oliver Zolk
, Julianne Byrne
, Helen Campbell
Marleen van den Berg
, Claire Berger
, Gabriele Calaminus
, Uta Dirksen
, Jeanette Falck Winther
Sophie D Fosså
, Desiree Grabow
, Riccardo Haupt
, Melanie Kaiser
, Tomas Kepak
, Leontien Kremer
, Dalit Modan-Moses
, Andreas Ranft
, Claudia Spix
, Peter Kaatsch
, Joop S. E. Laven
Eline van Dulmen-den Broeder
, André G. Uitterlinden
, Marry M. van den Heuvel-Eibrink
and on behalf of the
Background: Improved risk stratification, more effective therapy and better supportive care have resulted in survival
rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every
four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment
can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause
increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in
susceptibility to therapy related gonadal impairment suggests a role for genetic variation.
Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment
in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age
at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one
genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been
performed using endocrine measurements for gonadal impairment as the primary outcome in CCS.
Methods: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment
among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or
alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837
non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort
assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been
associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will
be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort.
Discussion: This international collaboration aims to enhance knowledge of genetic variation which may be included in
risk prediction models for gonadal impairment in CCS.
Keywords: Childhood cancer survivor, Genetic variations, SNPs, Late effects, GWAS
* Correspondence: email@example.com
Division of Reproductive Endocrinology and Infertility, Department of
Obstetrics and Gynecology, Erasmus MC –Sophia Children’s Hospital,
Rotterdam, The Netherlands
Department of Pediatric Hematology and Oncology, Erasmus MC –Sophia
Children’s Hospital, Rotterdam, The Netherlands
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
van der Kooi et al. BMC Cancer (2018) 18:930
As a result of continuous improvements in treatment
and supportive care, survival rates after childhood can-
cer have increased over the past decades, now reaching
80% in developed countries. However, the harsh treat-
ment components that have led to increased survival
rates can induce serious long-term complications. One
in every four childhood cancer survivors (CCS) reveals
severe or life-threatening adverse late effects , and
three in every four survivors report at least one late
effect [2,3]. In female CCS, apart from radiotherapy
involving the field of the ovaries or pituitary, alkylating
agents are important risk factors for fertility impairment
[4–7] and damage is dose-dependent . Such toxic
agents can damage the ovarian follicle pool severely,
leading to impaired fertility illustrated by an absent or
substantially shortened reproductive window. Conse-
quently, considering the current tendency in European
countries to postpone childbearing, female survivors may
find themselves involuntarily childless, leading to an in-
creased use of artificial reproductive techniques. The feasi-
bility to reach parenthood is of great significance to both
parents of children with cancer and to CCS, and is an im-
portant determinant of quality of life [9–14]. In addition,
gonadal impairment or early menopause carries adverse
health risks for women, such as an increased risk for car-
diovascular disease and osteoporosis, which require inten-
sive and long-term medical attention .
Variations in long-term gonadal impairment in CCS
who received the same treatment suggest that genetic
variation may be an important determinant of gonadal
impairment in CCS. Currently, only limited information
is available on the role of genetic factors in the develop-
ment of impaired gonadal reserve after childhood cancer
treatment . One single center study has been per-
formed which evaluated seven genetic single nucleotide
polymorphisms (SNPs) in 176 female CCS. These SNPs
were selected based on the fact that they have been
found to be associated with age at menopause in large
genome wide association studies (GWAS) in the general
female population [16,17]. While one of these allelic
variations in the BRSK1 gene (rs1172822) was found as-
sociated with a low anti-Müllerian hormone (AMH)
level in CCS , replication of this finding has not been
reported so far. Meanwhile, many more SNPs have been
reported to be associated with reproductive ageing in
the general population coming from large-scale collab-
orative consortia [18,19] but none have yet been investi-
gated in CCS. In order to identify independent genetic
determinants for therapy related gonadal impairment,
substantially sized cohorts with well-documented clinical
as well as treatment data are required. In addition, inde-
pendent replication cohorts must be available to validate
the results. One GWAS  has been performed (with
Affymetrix 6.0 SNP array) in the St. Jude Lifetime Cohort
Study (SJLIFE) among 799 ethnically mixed female CCS,
which included an independent replication cohort (geno-
typed with the Illumina Omni5 SNP array) of 1624 women
from the ethnically mixed Childhood Cancer Survivor
Study (CCSS). This GWAS did not identify a genome wide
significant hit, but found a SNP (rs9999820) that was bor-
derline significantly associated (p=3.3*10
creased risk of premature menopause, especially in the
subgroup of CCS who had undergone ovarian irradiation.
This haplotype, consisting of 4 SNPs, is associated with in-
creased hippocampal NPYR2 gene expresssion, which is as-
sociated with a neuroendocrine pathway . Noteworthy
is that this GWAS evaluated the genetic variation in (self--
reported) premature menopause, the latest manifestation of
gonadal impairment or ageing.
The PanCareLIFE initiative, a 5-year (2013–8) EU Frame-
work 7 Programme in the Health Theme originating from
the PanCare project, focuses on the identification of deter-
minants of long-term health of CCS. Specifically, PanCare-
LIFE will evaluate female gonadal impairment, hearing, and
quality of life. Investigators from sixteen partner institutions
from ten European countries have prospectively and retro-
spectively collected data from over 12,000 survivors from
cancer diagnosed before they were 25 years of age.
The current study is part of this European wide
endeavor and focuses on the identification of genetic fac-
tors which play a role in the risk of treatment-induced
gonadal impairment among female childhood cancer
survivors. Its specific objectives are to validate previously
identified genetic polymorphisms associated with
gonadal impairment in female childhood cancer survi-
vors, using a candidate gene approach; and to identify
novel SNPs that are independently associated with
chemotherapy induced gonadal impairment in female
childhood cancer survivors, using a GWAS.
For the current study we included female adult survivors
(≥18 years) of childhood cancer, diagnosed before the age
of 25 years, with a follow-up time of at least 5 years after
diagnosis. Eligible survivors had to have been treated with
chemotherapy. Exclusion criteria included radiotherapy
involving both ovaries, defined as bilateral irradiation of
the abdomen below the pelvic crest, or radiotherapy in-
volving the pituitary, defined as cranial or craniospinal ir-
radiation. Furthermore, survivors were not eligible if they
had undergone myeloablative allogeneic stem cell trans-
plantation, with or without total body irradiation.
PanCareLIFE consists of 8 work packages of which 5
focus on scientific work. Work package 4 encompasses
van der Kooi et al. BMC Cancer (2018) 18:930 Page 2 of 7
two parts: WP4a focuses on genetic variation in gonadal
impairment, and WP4b focuses on genetic variation in
ototoxicity. This study addresses work package 4a. For this
work package, adult female CCS were recruited in ten
institutions from seven countries (Fig. 1). The
participating institutions and included numbers were: the
Dutch Childhood Oncology Group (AMC, EMC, LUMC,
UMCG, UMCN, VUmc) (inclusions n= 306), Erasmus
Medical Center Rotterdam (n= 25) and VU Medical Cen-
ter Amsterdam (n= 19) from the Netherlands, Fakultni
Nemocnice Brno (n= 134) and Fakultni Nemocnice v
Motole (n= 86) from Czech Republic, Oslo University
Hospital Departments of Oncology/ Pediatrics (n=107)
from Norway, I.R.C.C.S. Giannina Gaslini (n= 67) from
Italy, Department of Paediatric Oncology/University
Hospital, St-Etienne (n= 64) from France, University
Hospital Muenster (n= 39) from Germany and Sheba
Medical Center (n= 18) from Israel. In total 865 CCS were
included in this study. DNA samples could not be col-
lected in 28 cases, leaving 837 CCS for analysis (Table 1).
Medical ethics approval for the study was obtained
from all relevant local committees and written informed
consent was obtained from all participants.
Basic demographic data of all participants (month and
year of birth and of follow-up), diagnostic data (month
and year of diagnosis, type of diagnosis) and full details
of cancer treatment were retrospectively collected from
medical databases and medical records. Data on cancer
treatment comprised of details on surgery, chemother-
apy and radiotherapy, including start and stop dates and
cumulative dosage. All data will be merged at the central
data center in Mainz likewise a former EU funded sister
project PanCareSurFup , and will finally be pseudo-
nymized for the investigators of this study.
The primary outcome of this study is AMH level. Serum
samples were centrifuged, stored at −20 °C and shipped
on dry ice to the VUmc Amsterdam where all AMH
levels were analysed in the same laboratory using an
ultra-sensitive Elecsys AMH assay (Roche Diagnostics
GmbH, Mannheim, Germany) at one time point. Data
on AMH levels were sent to the central data center in
Mainz and merged into the central database and subse-
quently pseudonymized to the investigators. In addition
to the continuous AMH levels, patients will be divided
in two groups based on AMH levels considered relevant
as a proxy for gonadal impairment, considering data on
AMH levels in healthy females measured with the same
assay in the reference laboratory in the VUmc
Amsterdam. These details will be described in detail in
the forthcoming manuscript. In addition, detailed
Fig. 1 Participating institutions throughout Europe and Israel
van der Kooi et al. BMC Cancer (2018) 18:930 Page 3 of 7
information about menstrual history, and/or FSH level,
and/or information on usage of artificial reproductive
techniques will be used to evaluate gonadal impairment.
Blood or saliva samples were obtained for DNA isola-
tion. Blood samples (n= 781) were stored at ≤−20 °C
and shipped on dry ice while saliva kits (n= 56) were
stored and shipped at room temperature. Genomic DNA
was extracted by the salting-out method. The choice of
genotyping array was made after extensive comparison
between all currently available arrays. The Infinium®
Global Screening Array was chosen based on the rich
up-to-date content and its suitability for GWAS includ-
ing rare variants, while also containing clinically relevant
content, including pharmacogenetics.
For the GWAS a genetic sample size calculation was
performed to estimate the number of cases required in
the current study . As it is impossible to estimate
the allelic frequencies in our population, the following
assumptions were made for the power calculation: 1) a
high risk allele frequency of 0.2, 2) a genome-wide sig-
nificant significance level (5*10
), 3) a cohort size larger
than n= 800 and 4) a case to control ratio of 1:2. Based
on these assumptions, we determined that the number
of recruited patients provided statistical power (80%) to
identify variants with an odds ratio of at least 1.8.
Quality control and imputations
A quality control (QC) protocol containing multiple filters
will be applied to clean the genetic data and to ensure its
quality prior to either imputations or analysis . Both a
SNP and individual call rate filter of 97.5% will be applied
to remove poorly genotyped SNPs and individuals from
the data. Furthermore, a Hardy-Weinberg Equilibrium test
(significance level < 1*10
) will be employed to remove
variants containing potential genotyping errors. To ensure
sample quality, samples with extreme heterozygosity,
gender mismatches, and familial relationships will be
assessed and removed. Genetic ancestry of the samples
will be assessed and corrected for using principal
Finally, imputations will be performed using the
Michigan Imputation Server using default settings .
The reference panel chosen for imputations is the
Haplotype Reference Consortium (HRC r1.1) . The
same approach has previously been used in large-scale
population studies such as the Rotterdam Study  and
Generation R .
For the candidate gene approach we will extract the
genotypes of a list of predetermined SNPs based on pub-
lished literature. The Mann-Whitney U test and the
Kruskal-Wallis test will be employed to compare the dis-
tribution between groups with continuous data. Logistic
regression will be performed to calculate the odds ratio
and 95% confidence interval of the SNPs to assess their
risk of gonadal impairment. This model will adjust for
several confounders: principal component analysis
(PCA) will be used to correct for population stratifica-
tion by modelling ancestry differences between cases
and controls . PCA is a common tool that has been
widely used for the combined analysis of correlated phe-
notypes in genetic linkage and association studies .
Furthermore, the model will adjust for cyclophospha-
mide equivalent dose (CED). This measure enables com-
parison of alkylating agent exposure independent of
drug dose distribution within a particular cohort (as the
formerly used alkylating agent dose), permitting
Table 1 Data providing institutions in genetic work package on gonadal impairment
Country Data provider Treatment data DNA samples
The Netherlands Dutch Childhood Oncology Group 306 298
Erasmus Medical Center, Rotterdam 25 24
VU Medical Center, Amsterdam 19 18
Czech Republic Fakultni Nemocnice Brno 134 132
Fakultni Nemocnice v Motole 86 81
Norway Oslo University Hospital 107 107
Italy I.R.C.C.S. Giannina Gaslini 67 64
France Center Hospitalier Universitaire de Saint-Étienne 64 58
Germany University Hospital Muenster, Germany 39 37
Israel Sheba Medical Center, Tel Hashomer 18 18
TOTAL 865 837
Dutch Childhood Oncology Group: Academic Medical Center in Amsterdam (AMC), Erasmus Medical Center in Rotterdam (EMC), Leiden University Medical Center
(LUMC), University Medical Center Groningen (UMCG), University Medical Center Nijmegen (UMCN), VU Medical Center (VUmc)
van der Kooi et al. BMC Cancer (2018) 18:930 Page 4 of 7
comparison across different cohorts . In addition,
linear regression will be performed to calculate the effect
of the SNPs on continuous AMH levels. This model will
include age, in addition to the principal components and
CED. The modifying effect of genetic predisposition on
the association between CED and gonadal impairment
will be also explored.
To identify relevant SNPs from the GWAS that
may be important but do not reach genome-wide sig-
nificance, we will use a suggestive significance level of
. After GWAS analysis, we will use the R
script EasyQC  to clean the association results
based, amongst others, on minor allele frequency and
imputation quality. The results will then be visualized
and the functional annotation for all leading SNPs
will be identified using the online platform called
Functional Mapping and Annotation of GWAS
For both the candidate gene approach and GWAS, to
ensure that associations are not a chance finding or an
artifact due to uncontrolled biases, associations will be
replicated within a replication cohort, based on the St.
Jude Lifetime Cohort Study (SJLIFE) from St. Jude
Children’s Research Hospital, Memphis USA [33,34]
and CCSS cohort.
This paper outlines the design of one study within the
PanCareLIFE initiative that has two separate research
aims. Female CCS from ten different institutions from
seven European countries will be included to validate
previously identified genetic polymorphisms associated
with gonadal impairment and to identify novel SNPs that
are independently associated with chemotherapy in-
duced gonadal impairment in female CCS.
Sufficiently-sized cohorts are of key importance in
genetic association studies in order to have adequate
power to identify low-risk variants. This is especially of
importance in the evaluation of common traits such as
gonadal function, where many common variants may
operate with small effect sizes. To this end, we per-
formed a power calculation to estimate the required co-
hort size for the current study, based on the estimated
allelic frequency in our population.
It is standard practice in current genetic association
studies to include an independent replication cohort to
validate findings from the initial discovery cohort. How-
ever, few large cohorts exist that have sufficient numbers
of female CCS, let alone with complete data as well as
stored DNA and AMH for analysis. For this project, a
collaboration with the St. Jude Children’s Research Hos-
pital, Memphis USA and CCSS has been initiated. AMH
levels will be measured in the same laboratory with the
same AMH assay for the discovery and replication co-
hort, thus minimizing lab variation. Given the (non-sig-
nificant) GWAS observations in the St Jude discovery
cohort we believe forces must be joined, and we are
therefore actively looking for additional cohorts to in-
clude in this and future international collaborations. We
encourage readers who are aware of such collections to
contact the corresponding author.
Gonadal impairment in CCS can be defined in many
ways [35–37], and especially in international collabora-
tions a clear consensus on the definition, as objective as
possible, is needed. A separate work package within the
PanCareLIFE consortium will combine seven criteria
and several different questionnaires to assess clinical go-
nadal status in 20,000 subjects. For the current study,
the primary endpoint AMH was chosen, which will be
evaluated both linear as categorized. The secondary end-
point is gonadal impairment based on detailed informa-
tion about menstrual history, FSH levels and
information on usage of artificial reproductive tech-
niques. AMH has the advantage to be as objective as
possible, in comparison to questionnaire data that may
be prone to recall bias or incorrect information given by
the survivor. In addition, AMH can serve as a reliable
surrogate marker for ovarian function while the primor-
dial follicle pool is not yet depleted [38,39]. The only re-
ported GWAS investigating therapy induced fertility
impairment in CCS, used premature menopause as pri-
mary outcome (clinically assessed in the discovery co-
hort and self-reported in the replication cohort) .
Prior to the clinical manifestation of amenorrhea and in-
creased levels of FSH, impaired gonadal function can be
detected by the measurement of lower serum AMH
levels . AMH in females is produced solely in the
ovary by granulosa cells of small growing follicles and is
considered a surrogate marker for ovarian function and
ovarian reserve [38,39]. Like the primordial follicle pool,
AMH levels decrease from adolescence on, until meno-
pause occurs. Even survivors who do not report prema-
ture menopause (or Primary Ovarian Insufficiency, POI,
defined as menopause before the age of 40 years) can
still have a poor ovarian function, potentially resulting in
reduced fertility or a shorter reproductive window (e.g.,
early menopause or menopause between 40 and
45 years). This impairment of gonadal function can be
identified by the evaluation of AMH levels.
In conclusion, we describe the design of a genetic as-
sociation study that will evaluate the association of gen-
etic variability with gonadal impairment in a European
cohort of childhood cancer survivors, with AMH levels
as the primary outcome measure. This international col-
laboration will enhance knowledge of genetic variation
which may be included in risk prediction models for
van der Kooi et al. BMC Cancer (2018) 18:930 Page 5 of 7
gonadal impairment in CCS. In the future, patients with
childhood cancer, parents and survivors may benefit
from better individualized counselling concerning future
fertility options and necessity for fertility preservation.
AMH: Anti-Müllerian hormone; CCS: Childhood cancer survivors;
CED: Cyclophosphamide equivalent dose; FSH: Follicle stimulating hormone;
GWAS: Genome wide association study; PCA: Principal component analysis;
SJLIFE: St. Jude Lifetime Cohort Study; SNP: Single nucleotide polymorphism
We thank all participating survivors of childhood cancer, without whom this study
would not be possible. In addition to the co-authors of this paper, the
PanCareLIFE consortium includes the following project partners: Pintail
Ltd., Dublin, Ireland (Kylie O’Brien), Universität zu Lübeck, Germany (Thorsten
Langer), Charité –Universitätsmedizin Berlin, Germany (Anja Borgmann-Staudt),
Westfälische Wilhelms-Universität Münster, Germany (Antoinette am Zehnhoff-
Dinnesen), Universität Bern, Switzerland (Claudia Kuehni) and Universitaetsklini-
kum Bonn, Bonn, Germany (Katja Baust). Data is, in addition to the institutions
of the co-authors, provided by: Netherlands Cancer Institute (Floor van Leeu-
wen), Helios Kliniken Berlin Buch, Germany (Gabriele Strauss), Istituto Giannina
Gaslini, Genoa, Italy (Dr. R Haupt, Dr. M-L Garré), Great Ormond Street Hospital
(Alison Leiper), Medizinische Universität Graz, Austria (H Lackner), Uniwersytet
Medyczny w Białymstoku, Bialystok, Poland (Anna Panasiuk, Maryna Krawczuk-
Rybak), Heinrich Heine Universität Düsseldorf, Germany (Marina Kunstreich), Uni-
versität Ulm, Germany (Holger Cario), Klinikum Stuttgart, Olgahospital, Stuttgart,
Germany (Stefan Bielack), Uniwersytet Gdánski, Poland (Joanna Stefanowicz),
University College London Hospital, UK (Victoria Grandage).
This work was supported by the PanCareLIFE project that has received
funding from the European Union’s Seventh Framework Programme for
research, technological development and demonstration under grant
agreement no 602030.
UD: German Cancer Aid grant 108128 to UD; ERA-Net-TRANSCAN consor-
tium, project number 01KT1310, and Euro Ewing Consortium EEC, project
number EU-FP7 602856, both funded under the European Commission
Seventh Framework Program FP7-HEALTH; Stiftung für krebskranke
Kinder in Essen. The funding bodies did not have a role in the design or
collection of data, neither will they have in analysis and interpretation of
AvdK wrote the manuscript. AvdK and EC coordinated the study and were
responsible for study logistics. MvdB, CB, GC, UD, AR, JF, SF, RH, TK, JK, EvD
and DM coordinated the study locally and were responsible for study
logistics, patient recruitment, and data collection at the various institutions.
JB, HC, DG, MK, CS and PK were involved in coordination and management
of the central data center and/or PanCareLIFE. LB and OZ were involved in
aspects of genetic statistical analyses. JL, LK, EvD, AU were involved in
aspects of conceptualization and study design. MvdH is the principal
investigator. All authors revised the manuscript critically for intellectual
content and have given final approval of the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
The PanCareLIFE study has been approved by the local ethics committees:
Kantonale Ethikkommission Bern, 362/2015; Comitate Etico Regionale,
507REG2014; Ethical Committee University Hospital Bno, June 11, 2016; Ethics
Committee Fakultni Nemocnice v Motole, Prague; De Videnskabsetiske
Komiteer Region Hovedstaden, H-1-2014-125; Ethikkommission Medizinische
Universität Graz, 27–015 ex 14/15; Ethikkommission der Universität Ulm, 160/
17; Ethikkommission der Universität zu Lübeck, 14/181; Ethik-Kommission der
Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität
Münster, 2014–619; Medische Ethische Toetsings Commissie Erasmus MC;
Medisch Ethische Toetsingscommissie, 2015_202. Written informed consent
was obtained from all participants.
Consent for publication
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Division of Reproductive Endocrinology and Infertility, Department of
Obstetrics and Gynecology, Erasmus MC –Sophia Children’s Hospital,
Rotterdam, The Netherlands.
Department of Pediatric Hematology and
Oncology, Erasmus MC –Sophia Children’s Hospital, Rotterdam, The
Princess Máxima Center for Pediatric Oncology, Lundlaan 6,
3584, EA, Utrecht, The Netherlands.
Department of Internal Medicine,
Erasmus MC, Rotterdam, The Netherlands.
Institute of Pharmacology of
Natural Products and Clinical Pharmacology, University Hospital Ulm, Ulm,
Boyne Research Institute, Drogheda, Ireland.
Pediatric Hematology and Oncology, VU Medical Center, Amsterdam, The
Department of Paediatric Oncology, University Hospital,
Epidemiology of Childhood and Adolescent Cancers,
CRESS, INSERM, UMR 1153, Paris Descartes University, Villejuif, France.
Department of Paediatric Haematology and Oncology, University Children’s
Hospital Bonn, University of Bonn Medical School, Bonn, Germany.
Pediatrics III, West German Cancer Centre, University Hospital Essen, Essen,
German Cancer Research Centre, DKTK, sites Bonn and Essen,
Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Clinical Medicine, Faculty of Health, Aarhus University,
Department of Oncology, Oslo University Hospital, Oslo,
German Childhood Cancer Registry, Institute of Medical
Biostatistics, Epidemiology and Informatics, University Medical Center, Mainz,
Epidemiology and Biostatistics Unit, Istituto Giannina Gaslini,
Czech Republic & International Clinical Research Center
(FNUSA-ICRC), University Hospital Brno, Brno, Czech Republic.
of Pediatrics, Academic Medical Center, Emma Children’s Hospital,
Amsterdam, The Netherlands.
Motol University Hospital, Prague, Czech
Chaim Sheba Medical Center, The Edmond and Lily Safra
Children’s Hospital, Tel Hashomer, Israel.
Sackler Faculty of Medicine,
Tel-Aviv University, Tel-Aviv, Israel.
Received: 19 March 2018 Accepted: 18 September 2018
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