OBJECTIVE: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENTS: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0 × 10-8) and 16 genome-wide suggestive (<5.0 × 10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.

Boyne Research Institute Bettystown Ireland

Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark; Department of Clinical Medicine Faculty of Health Aarhus University and University Hospital Aarhus Denmark

Department of Epidemiology and Cancer Control St Jude Children's Research Hospital Memphis Tennessee

Department of Epidemiology and Cancer Control St Jude Children's Research Hospital Memphis Tennessee; Division of Survivorship Department of Oncology St Jude Children's Research Hospital Memphis Tennessee

Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Haematology Radboud University Medical Center Nijmegen the Netherlands

Department of Internal Medicine Erasmus MC University Medical Center Rotterdam Rotterdam the Netherlands

Department of Obstetrics and Gynaecology Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Obstetrics and Gynaecology Radboud University Medical Center Nijmegen the Netherlands

Department of Obstetrics and Gynecology Erasmus MC University Medical Center Rotterdam the Netherlands

Department of Oncology Oslo University Hospital Oslo Norway

Department of Paediatric Oncology University Hospital Saint Etienne France; Lyon University Jean Monnet University INSERM Sainbiose Saint Etienne France

Department of Pediatric Hematology and Oncology Motol University Hospital Prague Czech Republic

Division of Childhood Cancer Epidemiology German Childhood Cancer Registry Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

Division of Pediatric Hematology and Oncology DOPO Clinic IRCCS Istituto Giannina Gaslini Via G Gaslini Genoa Italy

Institute of Clinical Pharmacology Brandenburg Medical School Theodor Fontane Immanuel Klinik Rüdersdorf Neuruppin Germany

Pediatrics 3 West German Cancer Centre University Hospital Essen Essen Germany; German Cancer Research Centre DKTK Sites Duesseldorf Essen Essen Germany

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Obstetrics and Gynecology Erasmus MC University Medical Center Rotterdam the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of pediatric oncology University of Groningen University Medical Center Groningen Groningen the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Reproductive Medicine University Medical Center Utrecht the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Division of Child Health Wilhelmina Children's Hospital University Medical Center Utrecht the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Emma Children's Hospital Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam the Netherlands

The Edmond and Lily Safra Children's Hospital Chaim Sheba Medical Center Tel Hashomer Israel; The Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

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

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