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

• Authors: VAN DER PERK Madeleine M E; BROER Linda; YASUI Yutaka; LAVEN Joop S E; ROBISON Leslie L; TISSING Wim J E; VERSLUYS Birgitta; BRESTERS Dorine; KASPERS Gertjan J L; LAMBALK Cornelis B; OVERBEEK Annelies; LOONEN Jacqueline J; BEERENDONK Catharina C M; BYRNE Julianne; BERGER Claire; CLEMENS Eva; VAN DULMEN-DEN BROEDER Eline; DIRKSEN Uta; VAN DER PAL Helena J; DE VRIES Andrica C H; WINTHER Jeanette Falck; RANFT Andreas; FOSSA Sophie D; GRABOW Desiree; MURACA Monica; KAISER Melanie; KEPÁK Tomáš; KRUSEOVA Jarmila; MODAN-MOSES Dalit; SPIX Claudia; ZOLK Oliver; KAATSCH Peter; KREMER Leontien C M; BROOKE Russell J; WANG Fan; BAEDKE Jessica L; UITTERLINDEN Andre G; BOS Annelies M E; VAN LEEUWEN Flora E; NESS Kirsten K; HUDSON Melissa M; VAN DER KOOI Anne-Lotte L F; VAN DEN HEUVEL-EIBRINK Marry M
• Year of publication: 2024
• Type: Article in Periodical
• Magazine / Source: Fertility and Sterility
• MU Faculty or unit: Faculty of Medicine
• web: https://www.sciencedirect.com/science/article/pii/S0015028224003121?via%3Dihub
• Doi: http://dx.doi.org/10.1016/j.fertnstert.2024.05.002
• Keywords: Ovarian reserve; gonadotoxicity; childhood cancer; survivorship; GWAS
• Description: Objective To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. Design Genome-wide association study. Setting Not applicable. Patients A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). Exposure Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. Main Outcome Measure Anti-M & uuml;llerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. Results Three genome-wide significant (<5.0 x 10(-8)) and 16 genome-wide suggestive (<5.0 x 10(-6)) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). Conclusion This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.