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Multicenter Study
. 2018 Sep 26;18(1):930.
doi: 10.1186/s12885-018-4834-3.

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

Anne-Lotte L F van der Kooi  1   2   3 , Eva Clemens  4   5 , Linda Broer  6 , Oliver Zolk  7 , Julianne Byrne  8 , Helen Campbell  8 , Marleen van den Berg  9 , Claire Berger  10   11 , Gabriele Calaminus  12 , Uta Dirksen  13   14 , Jeanette Falck Winther  15   16 , Sophie D Fosså  17 , Desiree Grabow  18 , Riccardo Haupt  19 , Melanie Kaiser  18 , Tomas Kepak  20 , Leontien Kremer  5   21 , Jarmila Kruseova  22 , Dalit Modan-Moses  23   24 , Andreas Ranft  13   14 , Claudia Spix  18 , Peter Kaatsch  18 , Joop S E Laven  25 , Eline van Dulmen-den Broeder  9 , André G Uitterlinden  6 , Marry M van den Heuvel-Eibrink  5 ; PanCareLIFE Consortium
Collaborators, Affiliations
Multicenter Study

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

Anne-Lotte L F van der Kooi et al. BMC Cancer. .

Abstract

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; GWAS; Genetic variations; Late effects; SNPs.

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Conflict of interest statement

Competing interest

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

Not applicable.

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Figures

Fig. 1
Fig. 1
Participating institutions throughout Europe and Israel
See this image and copyright information in PMC

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