Possible modification of BRSK1 on the risk of alkylating
chemotherapy-related reduced ovarian function

VAN DER KOOI, A. L. L. F., M. VAN DIJK, L. BROER, M. H. VAN DEN BERG, J. S. E . LAVEN, F. E. VAN LEEUWEN, C. B. LAMBALK, A. OVERBEEK, J. J . LOONEN, H. J. VAN DER PAL, W. J. TISSING, B. VERSLUYS, D. BRESTERS, C. C. M. BEERENDONK, C. R. RONCKERS, M. VAN DER HEIDEN-VAN DER LOO, G. L. KASPERS, A. C. H. DE VRIES, L. L. ROBISON, M. M. HUDSON, W. CHEMAITILLY, J. BYRNE, C. BERGER, E. CLEMENS, U. DIRKSEN, J. F. WINTHER, S. D. FOSSA, D. GRABOW, R. HAUPT, M. KAISER, Tomáš KEPÁK, J. KRUSEOVA, D. MODAN-MOSES, S. M. F. PLUIJM, C. SPIX, O. ZOLK, P. KAATSCH, J. H. KRIJTHE, L. C. KREMER, Y. YASUI, R. J. BROOKE, A. G. UITTERLINDEN, M. M. VAN DEN HEUVEL-EIBRINK and E. VAN DULMEN-DEN BROEDER. Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function. Human Reproduction. Oxford: Oxford Journals, 2021, vol. 36, No 4, p. 1120-1133. ISSN 0268-1161. Available from: https://dx.doi.org/10.1093/humrep/deaa342.

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TY  - JOUR
ID  - 1786881
AU  - Van der Kooi, A. L. L. F. - Van Dijk, M. - Broer, L. - Van den Berg, M. H. - Laven, J. S. E . - Van Leeuwen, F. E. - Lambalk, C. B. - Overbeek, A. - Loonen, J. J . - van der Pal, H. J. - Tissing, W. J. - Versluys, B. - Bresters, D. - Beerendonk, C. C. M. - Ronckers, C. R. - Van der Heiden-van der Loo, M. - Kaspers, G. L. - De Vries, A. C. H. - Robison, L. L. - Hudson, M. M. - Chemaitilly, W. - Byrne, J. - Berger, C. - Clemens, E. - Dirksen, U. - Winther, J. F. - Fossa, S. D. - Grabow, D. - Haupt, R. - Kaiser, M. - Kepák, Tomáš - Kruseova, J. - Modan-Moses, D. - Pluijm, S. M. F. - Spix, C. - Zolk, O. - Kaatsch, P. - Krijthe, J. H. - Kremer, L. C. - Yasui, Y. - Brooke, R. J. - Uitterlinden, A. G. - Van den Heuvel-Eibrink, M. M. - Van Dulmen-den Broeder, E.
PY  - 2021
TI  - Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function
JF  - Human Reproduction
VL  - 36
IS  - 4
SP  - 1120-1133
EP  - 1120-1133
PB  - Oxford Journals
SN  - 02681161
KW  - ovarian reserve
KW  - childhood cancer
KW  - survivorship
KW  - fertility
KW  - gonadotoxicity
UR  - https://academic.oup.com/humrep/article/36/4/1120/6134861
N2  - STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n =465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Miillerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P= 3.0 x 10(-4)) between rs11668344 of BRSK 1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score >= 8000 mg/m(2)), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer.
ER  -

Basic information
Original name	Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function
Authors	VAN DER KOOI, A. L. L. F. (guarantor), M. VAN DIJK, L. BROER, M. H. VAN DEN BERG, J. S. E . LAVEN, F. E. VAN LEEUWEN, C. B. LAMBALK, A. OVERBEEK, J. J . LOONEN, H. J. VAN DER PAL, W. J. TISSING, B. VERSLUYS, D. BRESTERS, C. C. M. BEERENDONK, C. R. RONCKERS, M. VAN DER HEIDEN-VAN DER LOO, G. L. KASPERS, A. C. H. DE VRIES, L. L. ROBISON, M. M. HUDSON, W. CHEMAITILLY, J. BYRNE, C. BERGER, E. CLEMENS, U. DIRKSEN, J. F. WINTHER, S. D. FOSSA, D. GRABOW, R. HAUPT, M. KAISER, Tomáš KEPÁK (203 Czech Republic, belonging to the institution), J. KRUSEOVA, D. MODAN-MOSES, S. M. F. PLUIJM, C. SPIX, O. ZOLK, P. KAATSCH, J. H. KRIJTHE, L. C. KREMER, Y. YASUI, R. J. BROOKE, A. G. UITTERLINDEN, M. M. VAN DEN HEUVEL-EIBRINK and E. VAN DULMEN-DEN BROEDER.
Edition	Human Reproduction, Oxford, Oxford Journals, 2021, 0268-1161.

Other information
Original language	English
Type of outcome	Article in a journal
Field of Study	30214 Obstetrics and gynaecology
Country of publisher	United Kingdom of Great Britain and Northern Ireland
Confidentiality degree	is not subject to a state or trade secret
WWW	URL
Impact factor	Impact factor: 6.353
RIV identification code	RIV/00216224:14110/21:00122128
Organization unit	Faculty of Medicine
Doi	http://dx.doi.org/10.1093/humrep/deaa342
UT WoS	000648942000029
Keywords in English	ovarian reserve; childhood cancer; survivorship; fertility; gonadotoxicity
Tags	14110321, rivok
Tags	International impact, Reviewed
Changed by	Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 19/8/2021 12:00.

Abstract

STUDY QUESTION: Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER: Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY: Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION: CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n =465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS: To evaluate ovarian function, anti-Miillerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Meta-analysis across the three independent cohorts showed a significant interaction effect (P= 3.0 x 10(-4)) between rs11668344 of BRSK 1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score >= 8000 mg/m(2)), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION: While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS: Further research, validating our findings and identifying additional risk contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer.

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Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian ...

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