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.

Boyne Research Institute Drogheda Ireland

Chaim Sheba Medical Center The Edmond and Lily Safra Children's Hospital Tel Hashomer Israel

Czech Republic and International Clinical Research Center University Hospital Brno Brno Czech Republic

Danish Cancer Society Research Center Copenhagen Denmark

Department of Clinical Medicine Faculty of Health Aarhus University Aarhus Denmark

Department of Internal Medicine Erasmus MC Rotterdam The Netherlands

Department of Oncology Oslo University Hospital Oslo Norway

Department of Paediatric Haematology and Oncology University Children's Hospital Bonn University of Bonn Medical School Bonn Germany

Department of Paediatric Oncology University Hospital St Etienne France

Department of Pediatric Hematology and Oncology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Department of Pediatric Hematology and Oncology VU Medical Center Amsterdam The Netherlands

Department of Pediatrics Academic Medical Center Emma Children's Hospital Amsterdam The Netherlands

Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Epidemiology and Biostatistics Unit Istituto Giannina Gaslini Genoa Italy

Epidemiology of Childhood and Adolescent Cancers CRESS INSERM UMR 1153 Paris Descartes University Villejuif France

German Cancer Research Centre DKTK sites Bonn and Essen Germany

German Childhood Cancer Registry Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center Mainz Germany

Institute of Pharmacology of Natural Products and Clinical Pharmacology University Hospital Ulm Ulm Germany

Motol University Hospital Prague Czech Republic

Pediatrics 3 West German Cancer Centre University Hospital Essen Essen Germany

Princess Máxima Center for Pediatric Oncology Lundlaan 6 3584 EA Utrecht The Netherlands

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

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Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE

Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach: Results from the PanCareLIFE Study

Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function

Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study