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; null On Behalf Of The PanCareLIFE Consortium

doi:10.3390/cancers13184598

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 DirksenJeanette 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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	4598
Journal	Cancers
Volume	13
Issue number	18
DOIs	https://doi.org/10.3390/cancers13184598
Publication status	Published - 13 Sept 2021

Keywords

Anti-Müllerian hormone
Candidate gene approach
Chemotherapy
Childhood cancer survivors
Cytochrome P450 genes
Ovarian function

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10.3390/cancers13184598

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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., ... On Behalf Of The PanCareLIFE Consortium (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. Cancers, 13(18), Article 4598. https://doi.org/10.3390/cancers13184598

@article{7ffb4bdbd3cd407791d1f962358e1507,

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",

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-M{\"u}llerian 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 = "Anti-M{\"u}llerian hormone, Candidate gene approach, Chemotherapy, Childhood cancer survivors, Cytochrome P450 genes, Ovarian function",

author = "{van der Perk}, {M E Madeleine} and Linda Broer and Yutaka Yasui and Robison, {Leslie L} and Hudson, {Melissa M} and Laven, {Joop S E} and {van der Pal}, {Helena J} and Tissing, {Wim J E} and Birgitta Versluys and Dorine Bresters and Kaspers, {Gertjan J L} and {de Vries}, {Andrica C H} and Lambalk, {Cornelis B} and Annelies Overbeek and Loonen, {Jacqueline J} and Beerendonk, {Catharina C M} and Julianne Byrne and Claire Berger and Eva Clemens and Uta Dirksen and {Falck Winther}, Jeanette and Foss{\aa}, {Sophie D} and Desiree Grabow and Monica Muraca and Melanie Kaiser and Tom{\'a}{\v s} Kep{\'a}k and Jarmila Kruseova and Dalit Modan-Moses and Claudia Spix and Oliver Zolk and Peter Kaatsch and Krijthe, {Jesse H} and Kremer, {Leontien C M} and Brooke, {Russell J} and Baedke, {Jessica L} and {van Schaik}, {Ron H N} and {van den Anker}, {John N} and Uitterlinden, {Andr{\'e} G} and Bos, {Annelies M E} and {van Leeuwen}, {Flora E} and {van Dulmen-den Broeder}, Eline and {van der Kooi}, {Anne-Lotte L F} and {van den Heuvel-Eibrink}, {Marry M} and {On Behalf Of The PanCareLIFE Consortium}",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = sep,

day = "13",

doi = "10.3390/cancers13184598",

language = "English",

volume = "13",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "18",

}

van der Perk, MEM, Broer, L, Yasui, Y, Robison, LL, Hudson, MM, Laven, JSE, van der Pal, HJ , Tissing, WJE, Versluys, B, Bresters, D, Kaspers, GJL, de Vries, ACH, Lambalk, CB, Overbeek, A, Loonen, JJ, Beerendonk, CCM, Byrne, J, Berger, C, Clemens, E, Dirksen, U, Falck Winther, J, Fosså, SD, Grabow, D, Muraca, M, Kaiser, M, Kepák, T, Kruseova, J, Modan-Moses, D, Spix, C, Zolk, O, Kaatsch, P, Krijthe, JH, Kremer, LCM, Brooke, RJ, Baedke, JL, van Schaik, RHN, van den Anker, JN, Uitterlinden, AG, Bos, AME, van Leeuwen, FE, van Dulmen-den Broeder, E, van der Kooi, A-LLF, van den Heuvel-Eibrink, MM & On Behalf Of The PanCareLIFE Consortium 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', Cancers, vol. 13, no. 18, 4598. https://doi.org/10.3390/cancers13184598

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 et al.
In: Cancers, Vol. 13, No. 18, 4598, 13.09.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Effect of Genetic Variation in CYP450 on Gonadal Impairment in a European Cohort of Female Childhood Cancer Survivors, Based on a Candidate Gene Approach

T2 - Results from the PanCareLIFE Study

AU - van der Perk, M E Madeleine

AU - Broer, Linda

AU - Yasui, Yutaka

AU - Robison, Leslie L

AU - Hudson, Melissa M

AU - Laven, Joop S E

AU - van der Pal, Helena J

AU - Tissing, Wim J E

AU - Versluys, Birgitta

AU - Bresters, Dorine

AU - Kaspers, Gertjan J L

AU - de Vries, Andrica C H

AU - Lambalk, Cornelis B

AU - Overbeek, Annelies

AU - Loonen, Jacqueline J

AU - Beerendonk, Catharina C M

AU - Byrne, Julianne

AU - Berger, Claire

AU - Clemens, Eva

AU - Dirksen, Uta

AU - Falck Winther, Jeanette

AU - Fosså, Sophie D

AU - Grabow, Desiree

AU - Muraca, Monica

AU - Kaiser, Melanie

AU - Kepák, Tomáš

AU - Kruseova, Jarmila

AU - Modan-Moses, Dalit

AU - Spix, Claudia

AU - Zolk, Oliver

AU - Kaatsch, Peter

AU - Krijthe, Jesse H

AU - Kremer, Leontien C M

AU - Brooke, Russell J

AU - Baedke, Jessica L

AU - van Schaik, Ron H N

AU - van den Anker, John N

AU - Uitterlinden, André G

AU - Bos, Annelies M E

AU - van Leeuwen, Flora E

AU - van Dulmen-den Broeder, Eline

AU - van der Kooi, Anne-Lotte L F

AU - van den Heuvel-Eibrink, Marry M

AU - On Behalf Of The PanCareLIFE Consortium, null

PY - 2021/9/13

Y1 - 2021/9/13

N2 - 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.

AB - 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.

KW - Anti-Müllerian hormone

KW - Candidate gene approach

KW - Chemotherapy

KW - Childhood cancer survivors

KW - Cytochrome P450 genes

KW - Ovarian function

UR - http://www.scopus.com/inward/record.url?scp=85115097007&partnerID=8YFLogxK

U2 - 10.3390/cancers13184598

DO - 10.3390/cancers13184598

M3 - Article

C2 - 34572825

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 18

M1 - 4598

ER -

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

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