Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function
Authors: van der Kooi Anne-Lotte L F , van Dijk Marloes , Broer Linda , van den Berg Marleen H , Laven Joop S E , van Leeuwen Flora E , Lambalk Cornelis B , Overbeek Annelies , Loonen Jacqueline J , van der Pal Helena J , Tissing Wim J , Versluys Birgitta , Bresters Dorine , Beerendonk Catharina C M , Ronckers Cécile R , van der Heiden-van der Loo Margriet , Kaspers Gertjan L , de Vries Andrica C H , Robison Leslie L , Hudson Melissa M , Chemaitilly Wassim , Byrne Julianne , Berger Claire , Clemens Eva , Dirksen Uta , Falck Winther Jeanette , Fosså Sophie D , Grabow Desiree , Haupt Riccardo , Kaiser Melanie , Kepak Tomas , Kruseova Jarmila , Modan-Moses Dalit , Pluijm Saskia M F , Spix Claudia , Zolk Oliver , Kaatsch Peter , Krijthe Jesse H , Kremer Leontien C , Yasui Yutaka , Brooke Russell J , Uitterlinden André G , van den Heuvel-Eibrink Marry M , van Dulmen-den Broeder Eline 
Published: November 2020

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-Müllerian 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 × 10−4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), 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.

STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests.

TRIAL REGISTRATION NUMBER
N/A.