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
van der Perk, M E Madeleine; Broer, Linda; Yasui, Yutaka; Robison, Leslie L; Hudson, Melissa M; Laven, Joop S E; van der Pal, Helena J; Tissing, Wim J E; Versluys, Birgitta; Bresters, Dorine; Kaspers, Gertjan J L; de Vries, Andrica C H; Lambalk, Cornelis B; Overbeek, Annelies; Loonen, Jacqueline J; Beerendonk, Catharina C M; Byrne, Julianne; Berger, Claire; Clemens, Eva; Dirksen, Uta; Falck Winther, Jeanette; Fosså, Sophie D; Grabow, Desiree; Muraca, Monica; Kaiser, Melanie; Kepák, Tomáš; Kruseova, Jarmila; Modan-Moses, Dalit; Spix, Claudia; Zolk, Oliver; Kaatsch, Peter; Krijthe, Jesse H; Kremer, Leontien C M; Brooke, Russell J; Baedke, Jessica L; van Schaik, Ron H N; van den Anker, John N; Uitterlinden, André G; Bos, Annelies M E; van Leeuwen, Flora E; van Dulmen-den Broeder, Eline; van der Kooi, Anne-Lotte L F; van den Heuvel-Eibrink, Marry M; On Behalf Of The PanCareLIFE Consortium
(2021) Cancers, volume 13, issue 18
(Article)
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
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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.
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Keywords: Anti-Müllerian hormone, Candidate gene approach, Chemotherapy, Childhood cancer survivors, Cytochrome P450 genes, Ovarian function, Oncology, Cancer Research, Journal Article
ISSN: 2072-6694
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: Funding: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no 602030. In addition, the DCOG‐LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006‐3622) and by the Children Cancer‐Free Foundation (Project no. 20) and the St Jude Lifetime Cohort study by NCI U01 CA195547. M.E.M. van der Perk is supported by funding from the Princess Máxima Center Foundation and Stichting Kinderoncologisch Centrum Rotterdam (sKOCR). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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