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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
MEM. van der Perk, L. Broer, Y. Yasui, LL. Robison, MM. Hudson, JSE. Laven, HJ. van der Pal, WJE. Tissing, B. Versluys, D. Bresters, GJL. Kaspers, ACH. de Vries, CB. Lambalk, A. Overbeek, JJ. Loonen, CCM. Beerendonk, J. Byrne, C. Berger, E....
Language English Country Switzerland
Document type Journal Article
Grant support
NA
Stichting Kinder Oncologisch Centrum Rotterdam
NA
Princess Máxima Center Foundation
602030
Seventh Framework Programme
20
Stichting Kinderen Kankervrij
VU 2006-3622.
KWF Kankerbestrijding
U01 CA195547
NCI NIH HHS - United States
NLK
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- Publication type
- Journal Article MeSH
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.
Boyne Research Institute 5 Bolton Square East Drogheda A92 RY6K Co Louth Ireland
Childhood Cancer Research Group Danish Cancer Society Research Center 2100 Copenhagen Denmark
Department of Epidemiology Netherlands Cancer Institute 1066 CX Amsterdam The Netherlands
Department of Haematology Radboud University Medical Center 6500 HB Nijmegen The Netherlands
Department of Intelligent Systems Delft University of Technology 2628 BL Delft The Netherlands
Department of Oncology Oslo University Hospital 0372 Oslo Norway
Department of Paediatric Oncology University Hospital 42 055 Saint Etienne France
Division of Clinical Pharmacology Children's National Hospital Washington DC 20010 USA
German Cancer Research Centre DKTK Site Essen 45147 Essen Germany
Lyon University Jean Monnet University INSERM U 1059 Sainbiose 42023 Saint Etienne France
Motol University Hospital 150 05 Prague Czech Republic
Princess Máxima Center for Pediatric Oncology 3584 CS Utrecht The Netherlands
University Hospital Essen Pediatrics 3 West German Cancer Centre 45147 Essen Germany
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