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.

Boyne Research Institute Drogheda Ireland

Brandenburg Medical School Neuruppin Germany

Danish Cancer Society Research Center Copenhagen Denmark

Department of Clinical Medicine Faculty of Health Aarhus University Aarhus Denmark

Department of Epidemiology and Cancer Control St Jude Children's Research Hospital Memphis TN USA

Department of Epidemiology Netherlands Cancer Institute Amsterdam The Netherlands

Department of Haematology Radboud University Medical Center Nijmegen The Netherlands

Department of Internal Medicine Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Obstetrics and Gynaecology Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Obstetrics and Gynaecology Radboud University Medical Center Nijmegen The Netherlands

Department of Oncology Oslo University Hospital Oslo Norway

Department of Oncology St Jude Children's Research Hospital Memphis TN USA

Department of Paediatric Oncology Haematology University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Paediatric Oncology University Hospital St Etienne France

Department of Paediatric Oncology Wilhelmina Children's Hospital University Medical Center Utrecht The Netherlands

Department of Pediatric oncology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Division of Endocrinology Department of Pediatric Medicine St Jude Children's Research Hospital Memphis TN USA

Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Erasmus MC University Medical Centre Rotterdam The Netherlands

DOPO Clinic IRCCS Istituto Giannina Gaslini Genova Italy

Dutch Childhood Oncology Group Utrecht The Netherlands

Emma Children's Hospital Amsterdam UMC Vrije Universiteit Amsterdam Paediatric Oncology Cancer Center Amsterdam Amsterdam The Netherlands

Epidemiology and Biostatistics Unit IRCCS Istituto Giannina Gaslini Genova Italy

Epidemiology of Childhood and Adolescent Cancers CRESS INSERM UMR 1153 Paris Descartes University Villejuif France

German Cancer Consortium DKTK Site Essen Essen Germany

German Childhood Cancer Registry Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center Mainz Germany

Institute for Computing and Information Sciences Radboud University Nijmegen The Netherlands

Institute of Pharmacology of Natural Products and Clinical Pharmacology University Hospital Ulm Ulm Germany

Motol University Hospital Prague Czech Republic

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

The Edmond and Lily Safra Children's Hospital Chaim Sheba Medical Center Tel Hashomer and the Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

University Hospital Brno International Clinical Research Center Masaryk University Brno Czech Republic

University Hospital Essen Pediatrics 3 West German Cancer Centre Essen Germany

Willem Alexander Children's Hospital Leiden University Medical Center Leiden The Netherlands

Zobrazit více v PubMed

Anderson RA, Brewster DH, Wood R, Nowell S, Fischbacher C, Kelsey TW, Wallace WHB.. The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod 2018;33:1281–1290. PubMed PMC

Anderson RA, Nelson SM, Wallace WH.. Measuring anti-Mullerian hormone for the assessment of ovarian reserve: when and for whom is it indicated? Maturitas 2012;71:28–33. PubMed

Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT.. Data quality control in genetic case-control association studies. Nat Protoc 2010;5:1564–1573. PubMed PMC

Bright NJ, Carling D, Thornton C.. Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation. J Biol Chem 2008;283:14946–14954. PubMed PMC

Brooke RJ, Im C, Wilson CL, Krasin MJ, Liu Q, Li Z, Sapkota Y, Moon W, Morton LM, Wu G. et al. A high-risk haplotype for premature menopause in childhood cancer survivors exposed to gonadotoxic therapy. J Natl Cancer Inst 2018;110:895–904. PubMed PMC

Byrne J, Grabow D, Campbell H, O'Brien K, Bielack S, Am Zehnhoff-Dinnesen A, Calaminus G, Kremer L, Langer T, van den Heuvel-Eibrink MM. et al. PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents. Eur J Cancer 2018;103:227–237. PubMed

Carrera AC, Alvarado-Kristensson M.. SADB kinases license centrosome replication. Cell Cycle 2009;8:4005–4006. PubMed

Carter J, Raviv L, Applegarth L, Ford JS, Josephs L, Grill E, Sklar C, Sonoda Y, Baser RE, Barakat RR.. A cross-sectional study of the psychosexual impact of cancer-related infertility in women: third-party reproductive assistance. J Cancer Surviv 2010;4:236–246. PubMed PMC

Charpentier AM, Chong AL, Gingras-Hill G, Ahmed S, Cigsar C, Gupta AA, Greenblatt E, Hodgson DC.. Anti-Mullerian hormone screening to assess ovarian reserve among female survivors of childhood cancer. J Cancer Surviv 2014;8:548–554. PubMed

Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Donaldson SS, Ginsberg JP, Kenney LB, Levine JM, Robison LL. et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016;17:567–576. PubMed PMC

Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, Vrieze SI, Chew EY, Levy S, McGue M. et al. Next-generation genotype imputation service and methods. Nat Genet 2016;48:1284–1287. PubMed PMC

Day FR, Ruth KS, Thompson DJ, Lunetta KL, Pervjakova N, Chasman DI, Stolk L, Finucane HK, Sulem P, Bulik-Sullivan B. et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 2015;47:1294–1303. PubMed PMC

Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, Sulem P, Ks Whalen R, Sarkar S, Albrecht AKE. et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet 2017;49:834–841. PubMed PMC

Depmann M, Broer SL, van der Schouw YT, Tehrani FR, Eijkemans MJ, Mol BW, Broekmans FJ.. Can we predict age at natural menopause using ovarian reserve tests or mother's age at menopause? A systematic literature review. Menopause 2016a;23:224–232. PubMed

Depmann M, Eijkemans MJ, Broer SL, Scheffer GJ, van Rooij IA, Laven JS, Broekmans FJ.. Does anti-Mullerian hormone predict menopause in the general population? Results of a prospective ongoing cohort study. Hum Reprod 2016b;31:1579–1587. PubMed

Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C. et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014;20:370–385. PubMed

Dolleman M, Faddy MJ, van Disseldorp J, van der Schouw YT, Messow CM, Leader B, Peeters PH, McConnachie A, Nelson SM, Broekmans FJ.. The relationship between anti-Mullerian hormone in women receiving fertility assessments and age at menopause in subfertile women: evidence from large population studies. J Clin Endocrinol Metab 2013;98:1946–1953. PubMed

Duffy C, Allen S.. Medical and psychosocial aspects of fertility after cancer. Cancer J 2009;15:27–33. PubMed PMC

Feng R, Sang Q, Kuang Y, Sun X, Yan Z, Zhang S, Shi J, Tian G, Luchniak A, Fukuda Y. et al. Mutations in TUBB8 and human oocyte meiotic arrest. N Engl J Med 2016;374:223–232. PubMed PMC

Freeman EW, Sammel MD, Lin H, Gracia CR.. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab 2012;97:1673–1680. PubMed PMC

Fu D, Calvo JA, Samson LD.. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 2012;12:104–120. PubMed PMC

Gassner D, Jung R.. First fully automated immunoassay for anti-Mullerian hormone. Clin Chem Lab Med 2014;52:1143–1152. PubMed

Green DM, Nolan VG, Goodman PJ, Whitton JA, Srivastava D, Leisenring WM, Neglia JP, Sklar CA, Kaste SC, Hudson MM. et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2014;61:53–67. PubMed PMC

Green DM, Sklar CA, Boice JD Jr, Mulvihill JJ, Whitton JA, Stovall M, Yasui Y.. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. JCO 2009;27:2374–2381. PubMed PMC

GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet 2013;45:580–585. PubMed PMC

Guainazzi A, Schärer OD.. Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy. Cell Mol Life Sci 2010;67:3683–3697. PubMed PMC

He C, Kraft P, Chasman DI, Buring JE, Chen C, Hankinson SE, Pare G, Chanock S, Ridker PM, Hunter DJ.. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010;128:515–527. PubMed PMC

Hudson MM, Ehrhardt MJ, Bhakta N, Baassiri M, Eissa H, Chemaitilly W, Green DM, Mulrooney DA, Armstrong GT, Brinkman TM. et al. Approach for classification and severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude Lifetime Cohort. Cancer Epidemiol Biomarkers Prev 2017;26:666–674. PubMed PMC

Hurov KE, Cotta-Ramusino C, Elledge SJ.. A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability. Genes Dev 2010;24:1939–1950. PubMed PMC

Ikram MA, Brusselle GGO, Murad SD, van Duijn CM, Franco OH, Goedegebure A, Klaver CCW, Nijsten TEC, Peeters RP, Stricker BH. et al. The Rotterdam Study: 2018 update on objectives, design and main results. Eur J Epidemiol 2017;32:807–850. PubMed PMC

Iliodromiti S, Anderson RA, Nelson SM.. Technical and performance characteristics of anti-Mullerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update 2015;21:698–710. PubMed

Jiang ZZ, Hu MW, Ma XS, Schatten H, Fan HY, Wang ZB, Sun QY.. LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. Oncotarget 2016;7:5738–5753. PubMed PMC

Jiang P, Zhang D.. Maternal embryonic leucine zipper kinase (MELK): a novel regulator in cell cycle control, embryonic development, and cancer. Int J Mol Sci 2013;14:21551–21560. PubMed PMC

Kondo N, Takahashi A, Ono K, Ohnishi T.. DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids 2010;2010:543531. PubMed PMC

Langeveld NE, Grootenhuis MA, Voute PA, de Haan RJ, van den Bos C.. Quality of life, self-esteem and worries in young adult survivors of childhood cancer. Psychooncology 2004;13:867–881. PubMed

Levine JM, Whitton JA, Ginsberg JP, Green DM, Leisenring WM, Stovall M, Robison LL, Armstrong GT, Sklar CA.. Nonsurgical premature menopause and reproductive implications in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 2018;124:1044–1052. PubMed PMC

Lie FS, Laven JS, Hakvoort-Cammel FG, Schipper I, Visser JA, Themmen AP, de Jong FHMM, vdH E.. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Mullerian hormone. Hum Reprod 2009;24:982–990. PubMed

Lu R, Niida H, Nakanishi M.. Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. J Biol Chem 2004;279:31164–31170. PubMed

Lunsford AJ, Whelan K, McCormick K, McLaren JF.. Antimullerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 2014;101:227–231. PubMed

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, Kang HM, Fuchsberger C, Danecek P, Sharp K. et al.; Haplotype Reference Consortium. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 2016;48:1279–1283. PubMed PMC

Medina-Gomez C, Felix JF, Estrada K, Peters MJ, Herrera L, Kruithof CJ, Duijts L, Hofman A, van Duijn CM, Uitterlinden AG. et al. Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study. Eur J Epidemiol 2015;30:317–330. PubMed PMC

Nelson SM, Messow MC, McConnachie A, Wallace H, Kelsey T, Fleming R, Anderson RA, Leader B.. External validation of nomogram for the decline in serum anti-Mullerian hormone in women: a population study of 15,834 infertility patients. Reprod Biomed Online 2011;23:204–206. PubMed

Overbeek A, van den Berg M, Kremer LCM, van den Heuvel-Eibrink MM, Tissing WJE, Loonen JJ, Versluys B, Bresters D, Kaspers GJL, Lambalk CB. et al. A nationwide study on reproductive function, ovarian reserve and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges. BMC Cancer 2012;12: PubMed PMC

Overbeek A, van den Berg MH, van Leeuwen FE, Kaspers GJL, Lambalk CB, van Dulmen-den Broeder E.. Chemotherapy-related late adverse effects on ovarian function in female survivors of childhood and young adult cancer: a systematic review. Cancer Treat Rev 2017;53:10–24. PubMed

Perry JRB, Corre T, Esko T, Chasman DI, Fischer K, Franceschini N, He C, Kutalik Z, Mangino M, Rose LM. et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013;22:1465–1472. PubMed PMC

Perry JR, Stolk L, Franceschini N, Lunetta KL, Zhai G, McArdle PF, Smith AV, Aspelund T, Bandinelli S, Boerwinkle E. et al. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet 2009;41:648–650. PubMed PMC

R Development Core Team. R: A Language and Environtment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2014.

Rodríguez-Asiain A, Ruiz-Babot G, Romero W, Cubí R, Erazo T, Biondi RM, Bayascas JR, Aguilera J, Gómez N, Gil C. et al. Brain Specific Kinase-1 BRSK1/SAD-B associates with lipid rafts: modulation of kinase activity by lipid environment. Biochim Biophys Acta 2011;1811:1124–1135. PubMed

Royston P, Altman DG.. Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. J R Stat Soc C (Appl Stat) 1994;43:429–467.

Sample V, Ramamurthy S, Gorshkov K, Ronnett GV, Zhang J.. Polarized activities of AMPK and BRSK in primary hippocampul neurons. Mol Biol Cell 2015;26:1935–1946. PubMed PMC

Shackelford DB, Shaw RJ.. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9:563–575. PubMed PMC

Stolk L, Zhai G, van Meurs JB, Verbiest MM, Visser JA, Estrada K, Rivadeneira F, Williams FM, Cherkas L, Deloukas P. et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 2009;41:645–647. PubMed PMC

Tehrani FR, Shakeri N, Solaymani-Dodaran M, Azizi F.. Predicting age at menopause from serum antimullerian hormone concentration. Menopause 2011;18:766–770. PubMed

Thélie A, Papillier P, Pennetier S, Perreau C, Traverso JM, Uzbekova S, Mermillod P, Joly C, Humblot P, Dalbiès-Tran R.. Differential regulation of abundance and deadenylation of maternal transcripts during bovine oocyte maturation in vitro and in vivo. BMC Dev Biol 2007;7:125. PubMed PMC

Thomas-Teinturier C, Allodji RS, Svetlova E, Frey MA, Oberlin O, Millischer AE, Epelboin S, Decanter C, Pacquement H, Tabone MD. et al. Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod 2015;30:1437–1446. PubMed

Trama A, Botta L, Foschi R, Ferrari A, Stiller C, Desandes E, Maule MM, Merletti F, Gatta G, Group E-W.. Survival of European adolescents and young adults diagnosed with cancer in 2000-07: population-based data from EUROCARE-5. Lancet Oncol 2016;17:896–906. PubMed

van Beek RD, van den Heuvel-Eibrink MM, Laven JSE, de Jong FH, Themmen APN, Hakvoort-Cammel FG, van den Bos C, van den Berg H, Pieters R, de Muinck Keizer-Schrama SMPF.. Anti-Mullerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood. J Clin Endocrinol Metab 2007;92:3869–3874. PubMed

van den Berg H, Repping S, van der Veen F.. Parental desire and acceptability of spermatogonial stem cell cryopreservation in boys with cancer. Hum Reprod 2007;22:594–597. PubMed

van den Berg MH, Overbeek A, Lambalk CB, Kaspers GJL, Bresters D, van den Heuvel-Eibrink MM, Kremer LC, Loonen JJ, van der Pal HJ, Ronckers CM. et al.; DCOG LATER-VEVO study group. Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve. Hum Reprod 2018;33:1474–1488. PubMed

van den Heuvel-Eibrink MM, van der Kooi A-LLF, Wallace WHB.. Fertility preservation in women. N Engl J Med 2018;378:399–400. PubMed

van der Kooi ALF, Kelsey TW, van den Heuvel-Eibrink MM, Laven JSE, Wallace WHB, Anderson RA.. Perinatal complications in female survivors of cancer: a systematic review and meta-analysis. Eur J Cancer 2019a;111:126–137. PubMed

van der Kooi ALF, van den Heuvel-Eibrink MM, van den Berg SAA, van Dorp W, Pluijm SMF, Laven JSE.. Changes in anti-Mullerian hormone and inhibin B in children treated for cancer. J Adolesc Young Adult Oncol 2019b;8:281–290. PubMed

van der Kooi AL, van den Heuvel-Eibrink MM, van Noortwijk A, Neggers SJ, Pluijm SM, van Dulmen-den Broeder E, van Dorp W, Laven JS.. Longitudinal follow-up in female childhood cancer survivors: no signs of accelerated ovarian function loss. Hum Reprod 2017;32:193–200. PubMed

van der Kooi A-LLF, Clemens E, Broer L, Zolk O, Byrne J, Campbell H, van den Berg M, Berger C, Calaminus G, Dirksen U. et al.; on behalf of the PanCareLIFE Consortium. Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol. BMC Cancer 2018;18:930. PubMed PMC

van Disseldorp J, Faddy MJ, Themmen AP, de Jong FH, Peeters PH, van der Schouw YT, Broekmans FJ.. Relationship of serum antimullerian hormone concentration to age at menopause. J Clin Endocrinol Metab 2008;93:2129–2134. PubMed

van Dorp W, van den Heuvel-Eibrink MM, Stolk L, Pieters R, Uitterlinden AG, Visser JA, Laven JS.. Genetic variation may modify ovarian reserve in female childhood cancer survivors. Hum Reprod 2013;28:1069–1076. PubMed

van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP, Schoot BC. et al.; on behalf of the OPTIMIST study group Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: the predicted poor responder. Hum Reprod 2017;32:2496–2505. PubMed

Ward LD, Kellis M.. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012;40:D930–D934. PubMed PMC

Warren Andersen S. Identifying biomarkers for risk of premature menopause among childhood cancer survivors may lead to targeted interventions and wellness strategies. J Natl Cancer Inst 2018;110:801–802. PubMed PMC

Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013;45:1238–1243. PubMed PMC

Zebrack BJ, Block R, Hayes-Lattin B, Embry L, Aguilar C, Meeske KA, Li Y, Butler M, Cole S.. Psychosocial service use and unmet need among recently diagnosed adolescent and young adult cancer patients. Cancer 2013;119:201–214. PubMed

Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT.. Data quality control in genetic case-control association studies. Nat Protoc 2010;5:1564–1573. PubMed PMC

Brooke RJ, Im C, Wilson CL, Krasin MJ, Liu Q, Li Z, Sapkota Y, Moon W, Morton LM, Wu G. et al. A high-risk haplotype for premature menopause in childhood cancer survivors exposed to gonadotoxic therapy. J Natl Cancer Inst 2018;110:895–904. PubMed PMC

Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, Vrieze SI, Chew EY, Levy S, McGue M. et al. Next-generation genotype imputation service and methods. Nat Genet 2016;48:1284–1287. PubMed PMC

Green DM, Nolan VG, Goodman PJ, Whitton JA, Srivastava D, Leisenring WM, Neglia JP, Sklar CA, Kaste SC, Hudson MM. et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2014;61:53–67. PubMed PMC

HaploReg v4.1. Broad Institute; 2019.

He C, Kraft P, Chasman DI, Buring JE, Chen C, Hankinson SE, Pare G, Chanock S, Ridker PM, Hunter DJ.. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010;128:515–527. PubMed PMC

Ikram MA, Brusselle GGO, Murad SD, van Duijn CM, Franco OH, Goedegebure A, Klaver CCW, Nijsten TEC, Peeters RP, Stricker BH. et al. The Rotterdam Study: 2018 update on objectives, design and main results. Eur J Epidemiol 2017;32:807–850. PubMed PMC

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, Kang HM, Fuchsberger C, Danecek P, Sharp K. et al.; Haplotype Reference Consortium. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 2016;48:1279–1283. PubMed PMC

Medina-Gomez C, Felix JF, Estrada K, Peters MJ, Herrera L, Kruithof CJ, Duijts L, Hofman A, van Duijn CM, Uitterlinden AG. et al. Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study. Eur J Epidemiol 2015;30:317–330. PubMed PMC

Perry JRB, Corre T, Esko T, Chasman DI, Fischer K, Franceschini N, He C, Kutalik Z, Mangino M, Rose LM. et al. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013;22:1465–1472. PubMed PMC

R Development Core Team. R: A Language and Environtment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2014.

Royston P, Altman DG.. Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. J R Stat Soc C (Appl Stat )1994;43:429–467.

Stolk L, Zhai G, van Meurs JB, Verbiest MM, Visser JA, Estrada K, Rivadeneira F, Williams FM, Cherkas L, Deloukas P. et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 2009;41:645–647. PubMed PMC

van Dorp W, van den Heuvel-Eibrink MM, Stolk L, Pieters R, Uitterlinden AG, Visser JA, Laven JS.. Genetic variation may modify ovarian reserve in female childhood cancer survivors. Hum Reprod 2013;28:1069–1076. PubMed

Bright NJ, Carling D, Thornton C.. Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation. J Biol Chem 2008;283:14946–14954. PubMed PMC

Carrera AC, Alvarado-Kristensson M.. SADB kinases license centrosome replication. Cell Cycle 2009;8:4005–4006. PubMed

Feng R, Sang Q, Kuang Y, Sun X, Yan Z, Zhang S, Shi J, Tian G, Luchniak A, Fukuda Y. et al. Mutations in TUBB8 and human oocyte meiotic arrest. N Engl J Med 2016;374:223–232. PubMed PMC

GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet 2013;45:580–585. PubMed PMC

Hurov KE, Cotta-Ramusino C, Elledge SJ.. A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability. Genes Dev 2010;24:1939–1950. PubMed PMC

Jiang ZZ, Hu MW, Ma XS, Schatten H, Fan HY, Wang ZB, Sun QY.. LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. Oncotarget 2016;7:5738–5753. PubMed PMC

Jiang P, Zhang D.. Maternal embryonic leucine zipper kinase (MELK): a novel regulator in cell cycle control, embryonic development, and cancer. Int J Mol Sci 2013;14:21551–21560. PubMed PMC

Lu R, Niida H, Nakanishi M.. Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. J Biol Chem 2004;279:31164–31170. PubMed

Rodríguez-Asiain A, Ruiz-Babot G, Romero W, Cubí R, Erazo T, Biondi RM, Bayascas JR, Aguilera J, Gómez N, Gil C. et al. Brain specific kinase-1 BRSK1/SAD-B associates with lipid rafts: modulation of kinase activity by lipid environment. Biochim Biophys Acta 2011;1811:1124–1135. PubMed

Sample V, Ramamurthy S, Gorshkov K, Ronnett GV, Zhang J.. Polarized activities of AMPK and BRSK in primary hippocampul neurons. Mol Biol Cell 2015;26:1935–1946. PubMed PMC

Shackelford DB, Shaw RJ.. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9:563–575. PubMed PMC

Thélie A, Papillier P, Pennetier S, Perreau C, Traverso JM, Uzbekova S, Mermillod P, Joly C, Humblot P, Dalbiès-Tran R.. Differential regulation of abundance and deadenylation of maternal transcripts during bovine oocyte maturation in vitro and in vivo. BMC Dev Biol 2007;7:125. PubMed PMC

Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE

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