학술논문
Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.
Document Type
Academic Journal
Author
van der Perk MEM; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands. Electronic address: m.e.m.vanderperk@prinsesmaximacentrum.nl.; Broer L; Department of Internal Medicine, Rotterdam, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.; Yasui Y; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Laven JSE; Department of Obstetrics and Gynecology, Erasmus MC-University Medical Center, 3015 GD Rotterdam, The Netherlands.; Robison LL; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Tissing WJE; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Department of pediatric oncology, University of Groningen, University Medical Center Groningen, Groningen ,The Netherlands.; Versluys B; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; Bresters D; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; Kaspers GJL; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Lambalk CB; Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Overbeek A; Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Loonen JJ; Department of Haematology, Radboud University Medical Center, 6500HB Nijmegen, The Netherlands.; Beerendonk CCM; Department of Obstetrics and Gynaecology, Radboud University Medical Center, 6500HB Nijmegen, The Netherlands.; Byrne J; Boyne Research Institute, 1 The Maples, Bettystown, Co. Meath A92C635, Ireland.; Berger C; Department of Paediatric Oncology, University Hospital, 42 055 St-Etienne, France; Lyon University, Jean Monnet University, INSERM, U 1059, Sainbiose, Saint-Etienne, France.; Clemens E; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; van Dulmen-den Broeder E; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Dirksen U; University Hospital Essen, Pediatrics III, West German Cancer Centre, 45147 Essen, Germany; German Cancer Research Centre, DKTK, Sites Duesseldorf-Essen, 45147 Essen, Germany.; van der Pal HJ; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; de Vries ACH; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; Winther JF; Danish Cancer Society Research Center, Childhood Cancer Research Group, DK-2100 Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, 8200 Aarhus, Denmark.; Ranft A; University Hospital Essen, Pediatrics III, West German Cancer Centre, 45147 Essen, Germany; German Cancer Research Centre, DKTK, Sites Duesseldorf-Essen, 45147 Essen, Germany.; Fosså SD; Department of Oncology, Oslo University Hospital, 0372 Oslo, Norway.; Grabow D; Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.; Muraca M; DOPO Clinic, Division of Pediatric Hematology and Oncology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini, 5, 16147 Genoa, Italy.; Kaiser M; Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.; Kepák T; University Hospital Brno, International Clinical Research Center (FNUSA-ICRC), Masaryk University, 656 91 Brno, Czech Republic.; Kruseova J; Motol University Hospital, 150 05 Prague, Czech Republic.; Modan-Moses D; The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.; Spix C; Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.; Zolk O; Institute of Clinical Pharmacology, Brandenburg Medical School Theodor Fontane, Immanuel Klinik Rüdersdorf, 16816 Neuruppin, Germany.; Kaatsch P; Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.; Kremer LCM; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.; Brooke RJ; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Wang F; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Baedke JL; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Uitterlinden AG; Department of Internal Medicine, Rotterdam, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.; Bos AME; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Department of Reproductive Medicine, University Medical Center Utrecht, The Netherland.; van Leeuwen FE; Department of Epidemiology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.; Ness KK; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; Hudson MM; Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, Division of Survivorship, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.; van der Kooi ALF; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Department of Obstetrics and Gynecology, Erasmus MC-University Medical Center, 3015 GD Rotterdam, The Netherlands.; van den Heuvel-Eibrink MM; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; Division of Child Health, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Source
Publisher: Elsevier for the American Society for Reproductive Medicine Country of Publication: United States NLM ID: 0372772 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1556-5653 (Electronic) Linking ISSN: 00150282 NLM ISO Abbreviation: Fertil Steril Subsets: MEDLINE
Subject
Language
English
Abstract
Objective: We aimed 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.
Subjects: 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 nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-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 inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure.
Intervention: No intervention was performed.
Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis.
Results: Three genome-wide significant (<5.0x10-8 ) and 16 genome-wide suggestive (<5.0x10 -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. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10 -6 ), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10 -8 ).
Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As 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 and as well as fertility preservation options for childhood cancer survivors.
(Copyright © 2024. Published by Elsevier Inc.)
Design: Genome-wide association study.
Subjects: 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 nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-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 inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure.
Intervention: No intervention was performed.
Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis.
Results: Three genome-wide significant (<5.0x10
Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As 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 and as well as fertility preservation options for childhood cancer survivors.
(Copyright © 2024. Published by Elsevier Inc.)