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

J 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

VAN DER PERK, M. E. M., L. BROER, Y. YASUI, L. L. ROBISON, M. M. HUDSON et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

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

Abstract

V originále

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.

Citovat

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.

@article{1834257,
   author = {van der Perk, M. E. M. and Broer, L. and Yasui, Y. and Robison, L. L. and Hudson, M. M. and Laven, J. S. E. and van der Pal, H. J. and Tissing, W. J. E. and Versluys, B. and Bresters, D. and Kaspers, G. J. L. and de Vries, A. C. H. and Lambalk, C. B. and Overbeek, A. and Loonen, J. J. and Beerendonk, C. C. M. and Byrne, J. and Berger, C. and Clemens, E. and Dirksen, U. and Winther, J. F. and Fossa, S. D. and Grabow, D. and Muraca, M. and Kaiser, M. and Kepák, Tomáš and Kruseova, J. and ModanandMoses, D. and Spix, C. and Zolk, O. and Kaatsch, P. and Krijthe, J. H. and Kremer, L. C. M. and Brooke, R. J. and Baedke, J. L. and van Schaik, R. H. N . and van den Anker, J. N. and Uitterlinden, A. G. and Bos, A. M. E. and van Leeuwen, F. E. and Van Dulmenandden Broeder, E. and Van der Kooi, A. L. L. F. and Van den HeuvelandEibrink, M. M.},
   article_location = {BASEL},
   article_number = {18},
   doi = {http://dx.doi.org/10.3390/cancers13184598},
   keywords = {childhood cancer survivors; ovarian function; anti-Mullerian hormone; chemotherapy; candidate gene approach; cytochrome P450 genes},
   language = {eng},
   issn = {2072-6694},
   journal = {Cancers},
   title = {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},
   url = {https://www.mdpi.com/2072-6694/13/18/4598},
   volume = {13},
   year = {2021}
}

TY  - JOUR
ID  - 1834257
AU  - van der Perk, M. E. M. - Broer, L. - Yasui, Y. - Robison, L. L. - Hudson, M. M. - Laven, J. S. E. - van der Pal, H. J. - Tissing, W. J. E. - Versluys, B. - Bresters, D. - Kaspers, G. J. L. - de Vries, A. C. H. - Lambalk, C. B. - Overbeek, A. - Loonen, J. J. - Beerendonk, C. C. M. - Byrne, J. - Berger, C. - Clemens, E. - Dirksen, U. - Winther, J. F. - Fossa, S. D. - Grabow, D. - Muraca, M. - Kaiser, M. - Kepák, Tomáš - Kruseova, J. - Modan-Moses, D. - Spix, C. - Zolk, O. - Kaatsch, P. - Krijthe, J. H. - Kremer, L. C. M. - Brooke, R. J. - Baedke, J. L. - van Schaik, R. H. N . - van den Anker, J. N. - Uitterlinden, A. G. - Bos, A. M. E. - van Leeuwen, F. E. - Van Dulmen-den Broeder, E. - Van der Kooi, A. L. L. F. - Van den Heuvel-Eibrink, M. M.
PY  - 2021
TI  - 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
JF  - Cancers
VL  - 13
IS  - 18
SP  - 1-21
EP  - 1-21
PB  - MDPI
SN  - 20726694
KW  - childhood cancer survivors
KW  - ovarian function
KW  - anti-Mullerian hormone
KW  - chemotherapy
KW  - candidate gene approach
KW  - cytochrome P450 genes
UR  - https://www.mdpi.com/2072-6694/13/18/4598
N2  - 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.
ER  -

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. \textit{Cancers}. BASEL: MDPI, 2021, vol.~13, No~18, p.~1-21. ISSN~2072-6694. Available from: https://dx.doi.org/10.3390/cancers13184598.

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