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. M., L. BROER, Y. YASUI, L. L. ROBISON, M. M. HUDSON, J. S. E. LAVEN, H. J. VAN DER PAL, W. J. E. TISSING, B. VERSLUYS, D. BRESTERS, G. J. L. KASPERS, A. C. H. DE VRIES, C. B. LAMBALK, A. OVERBEEK, J. J. LOONEN, C. C. M. BEERENDONK, J. BYRNE, C. BERGER, E. CLEMENS, U. DIRKSEN, J. F. WINTHER, S. D. FOSSA, D. GRABOW, M. MURACA, M. KAISER, Tomáš KEPÁK, J. KRUSEOVA, D. MODAN-MOSES, C. SPIX, O. ZOLK, P. KAATSCH, J. H. KRIJTHE, L. C. M. KREMER, R. J. BROOKE, J. L. BAEDKE, R. H. N . VAN SCHAIK, J. N. VAN DEN ANKER, A. G. UITTERLINDEN, A. M. E. BOS, F. E. VAN LEEUWEN, E. VAN DULMEN-DEN BROEDER, A. L. L. F. VAN DER KOOI and M. M. VAN DEN HEUVEL-EIBRINK. 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. Cancers. BASEL: MDPI, 2021, vol. 13, No 18, p. 1-21. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers13184598.

Basic information

• Original name: 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
• Authors: VAN DER PERK, M. E. M. (guarantor), L. BROER, Y. YASUI, L. L. ROBISON, M. M. HUDSON, J. S. E. LAVEN, H. J. VAN DER PAL, W. J. E. TISSING, B. VERSLUYS, D. BRESTERS, G. J. L. KASPERS, A. C. H. DE VRIES, C. B. LAMBALK, A. OVERBEEK, J. J. LOONEN, C. C. M. BEERENDONK, J. BYRNE, C. BERGER, E. CLEMENS, U. DIRKSEN, J. F. WINTHER, S. D. FOSSA, D. GRABOW, M. MURACA, M. KAISER, Tomáš KEPÁK (203 Czech Republic, belonging to the institution), J. KRUSEOVA, D. MODAN-MOSES, C. SPIX, O. ZOLK, P. KAATSCH, J. H. KRIJTHE, L. C. M. KREMER, R. J. BROOKE, J. L. BAEDKE, R. H. N . VAN SCHAIK, J. N. VAN DEN ANKER, A. G. UITTERLINDEN, A. M. E. BOS, F. E. VAN LEEUWEN, E. VAN DULMEN-DEN BROEDER, A. L. L. F. VAN DER KOOI and M. M. VAN DEN HEUVEL-EIBRINK.
• Edition: Cancers, BASEL, MDPI, 2021, 2072-6694.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30204 Oncology
• Country of publisher: Switzerland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 6.575
• RIV identification code: RIV/00216224:14110/21:00124148
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.3390/cancers13184598
• UT WoS: 000699234000001
• Keywords in English: childhood cancer survivors; ovarian function; anti-Mullerian hormone; chemotherapy; candidate gene approach; cytochrome P450 genes
• Tags: 14110321, rivok
• Tags: International impact, Reviewed

Abstract

Simple Summary Childhood cancer patients receiving treatment containing alkylating agents are at risk of infertility, yet inter-individual variability in treatment-related ovarian damage is observed. Alkylating agents are metabolized by cytochrome P450 (CYP450) enzymes and polymorphisms in these CYP450 enzymes may explain this variability in ovarian damage. This study on genetic variation in CYP450 enzymes of chemotherapy-induced gonadotoxicity, using anti-Mullerian hormone (AMH) levels as a proxy for ovarian reserve, in female childhood cancer survivors (CCSs) may identify patients at risk of infertility. This unique global collaboration of two large CCS studies shows the significant gonadotoxic effect of enzyme CYP3A4*3 and significant protective effect of CYP2B6*2 on gonadal function in CCSs receiving alkylating agents. Genetic variation in CYP3A4 and CYP2B6 have previously been associated with gonadotoxicity after cancer treatment. These findings could guide risk prediction models determining patients at risk of chemotherapy-induced gonadal impairment. 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-Mullerian 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 x 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/m(2) 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.