Cancers (Sep 2021)
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
- M. E. Madeleine van der Perk,
- Linda Broer,
- Yutaka Yasui,
- Leslie L. Robison,
- Melissa M. Hudson,
- Joop S. E. Laven,
- Helena J. van der Pal,
- Wim J. E. Tissing,
- Birgitta Versluys,
- Dorine Bresters,
- Gertjan J. L. Kaspers,
- Andrica C. H. de Vries,
- Cornelis B. Lambalk,
- Annelies Overbeek,
- Jacqueline J. Loonen,
- Catharina C. M. Beerendonk,
- Julianne Byrne,
- Claire Berger,
- Eva Clemens,
- Uta Dirksen,
- Jeanette Falck Winther,
- Sophie D. Fosså,
- Desiree Grabow,
- Monica Muraca,
- Melanie Kaiser,
- Tomáš Kepák,
- Jarmila Kruseova,
- Dalit Modan-Moses,
- Claudia Spix,
- Oliver Zolk,
- Peter Kaatsch,
- Jesse H. Krijthe,
- Leontien C. M. Kremer,
- Russell J. Brooke,
- Jessica L. Baedke,
- Ron H. N. van Schaik,
- John N. van den Anker,
- André G. Uitterlinden,
- Annelies M. E. Bos,
- Flora E. van Leeuwen,
- Eline van Dulmen-den Broeder,
- Anne-Lotte L. F. van der Kooi,
- Marry M. van den Heuvel-Eibrink,
- on behalf of the PanCareLIFE Consortium
Affiliations
- M. E. Madeleine van der Perk
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Linda Broer
- Department of Internal Medicine, Rotterdam, ErasmusMC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- Yutaka Yasui
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Leslie L. Robison
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Melissa M. Hudson
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Joop S. E. Laven
- Department of Obstetrics and Gynecology, Erasmus MC–University Medical Center, 3015 GD Rotterdam, The Netherlands
- Helena J. van der Pal
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Wim J. E. Tissing
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Birgitta Versluys
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Dorine Bresters
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Gertjan J. L. Kaspers
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Andrica C. H. de Vries
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Cornelis B. Lambalk
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Annelies Overbeek
- Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Jacqueline J. Loonen
- Department of Haematology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Catharina C. M. Beerendonk
- Department of Obstetrics and Gynaecology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
- Julianne Byrne
- Boyne Research Institute, 5 Bolton Square, East, Drogheda, A92 RY6K Co. Louth, Ireland
- Claire Berger
- Department of Paediatric Oncology, University Hospital, 42 055 Saint-Etienne, France
- Eva Clemens
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Uta Dirksen
- University Hospital Essen, Pediatrics III, West German Cancer Centre, 45147 Essen, Germany
- Jeanette Falck Winther
- Childhood Cancer Research Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
- Sophie D. Fosså
- Department of Oncology, Oslo University Hospital, 0372 Oslo, Norway
- Desiree Grabow
- 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
- Monica Muraca
- Epidemiology and Biostatistics Unit and DOPO Clinic, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
- Melanie Kaiser
- 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
- Tomáš Kepák
- University Hospital Brno, International Clinical Research Center (FNUSA-ICRC), Masaryk University, 656 91 Brno, Czech Republic
- Jarmila Kruseova
- Motol University Hospital, 150 05 Prague, Czech Republic
- Dalit Modan-Moses
- 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
- Claudia Spix
- 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
- Oliver Zolk
- Institute of Clinical Pharmacology, Brandenburg Medical School Theodor Fontane, Immanuel Klinik Rüdersdorf, 16816 Neuruppin, Germany
- Peter Kaatsch
- 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
- Jesse H. Krijthe
- Department of Intelligent Systems, Delft University of Technology, 2628 BL Delft, The Netherlands
- Leontien C. M. Kremer
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Russell J. Brooke
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Jessica L. Baedke
- Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Ron H. N. van Schaik
- Department of clinical chemistry, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- John N. van den Anker
- Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC 20010, USA
- André G. Uitterlinden
- Department of Internal Medicine, Rotterdam, ErasmusMC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- Annelies M. E. Bos
- Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, 3584 CS Utrecht, The Netherlands
- Flora E. van Leeuwen
- Department of Epidemiology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Eline van Dulmen-den Broeder
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Anne-Lotte L. F. van der Kooi
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- Marry M. van den Heuvel-Eibrink
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
- on behalf of the PanCareLIFE Consortium
- DOI
- https://doi.org/10.3390/cancers13184598
- Journal volume & issue
-
Vol. 13,
no. 18
p. 4598
Abstract
Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743; age (years): median 25.8, interquartile range (IQR) 22.1–30.6). Using two additive genetic models in linear and logistic regression, nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) score and their impact on AMH levels. The main model evaluated the effect of the variant on AMH and the interaction model evaluated the modifying effect of the variant on the impact of CED score on log-transformed AMH levels. Results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (n = 391; age (years): median 31.3, IQR 26.6–37.4). Results: CYP3A4*3 was significantly associated with AMH levels in the discovery and replication cohort. Meta-analysis revealed a significant main deleterious effect (Beta (95% CI): −0.706 (−1.11–−0.298), p-value = 7 × 10−4) of CYP3A4*3 (rs4986910) on log-transformed AMH levels. CYP2B6*2 (rs8192709) showed a significant protective interaction effect (Beta (95% CI): 0.527 (0.126–0.928), p-value = 0.01) on log-transformed AMH levels in CCSs receiving more than 8000 mg/m2 CED. Conclusions: Female CCSs CYP3A4*3 carriers had significantly lower AMH levels, and CYP2B6*2 may have a protective effect on AMH levels. Identification of risk-contributing variants may improve individualized counselling regarding the treatment-related risk of infertility and fertility preservation options.
Keywords
- childhood cancer survivors
- ovarian function
- anti-Müllerian hormone
- chemotherapy
- candidate gene approach
- cytochrome P450 genes
