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

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-Müllerian 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 × 10 ^-8 ) and 16 genome-wide suggestive (<5.0 × 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.
Competing Interests: Declaration of Interests M.E.M.v.d.P. reports funding from European Union’s Seventh Framework Programme for research (technological development, and demonstration funding), Dutch Cancer Society (grant no. VU 2006-3622), Princess Máxima Center Foundation, and Stichting Kinderoncologisch Centrum Rotterdam (sKOCR), 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. L.B. has nothing to disclose. Y.Y. reports funding from National Cancer Institute (NCI) U01CA195547 (MPI: Hudson/Ness), St. Jude Lifetime Cohort Study (SJLIFE), NCI P30CA021765 (PI: Roberts) Cancer Center Support Grant (CCSG), and American Lebanese Syrian Associated Charities for the submitted work; funding from NCI U24CA055727 (PI: Armstrong) Childhood Cancer Survivor Study (CCSS), National Institutes of Health (NIH) R03DE029238 (PI: Li/Sun) Innovative Statistical Analysis for Genome-Wide Data with General Interval Censored Outcomes of Oral Health in Childhood Cancer Survivors, NCI R01CA216354 (MPI: Yasui/Zhang) Late Effects Prediction Using Clinical Phenotypes and Whole Genome Sequencing, St Jude Lifetime Cohort study by NCI U01 CA195547, NCI R01CA270157 (MPI: Bhakta/Yasui) Measuring Lifelong Multimorbidity with Patient Perspectives: Implementing and Visualizing the Cumulative Burden Methodology Across Cohorts, NCI R01CA258193 (MPI: Huang/Yasui) Patient-Generated Health Data to Predict Childhood Cancer Survivorship Outcomes (HEALTHSHARE), NIH &MD Anderson Cancer Center R01CA261750-01A1 (MPI: Howell/Mulrooney/Yasui) Personalized Risk Prediction to Reduce Cardiovascular Disease in Childhood Cancer Survivors, NCI &Northwestern University R01CA261898 (MPI: Burridge/Sapkota) Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children, NC. J.S.E.L. has nothing to disclose. L.L.R. has nothing to disclose. W.J.E.T. has nothing to disclose. B.V. has nothing to disclose. B.V. has nothing to disclose. D.B. has nothing to disclose. G.J.L.K. has nothing to disclose. C.B.L. has nothing to disclose. A.O. has nothing to disclose. J.J.L. has nothing to disclose. C.C.M.B. has nothing to disclose. J.B. has nothing to disclose. C.B. has nothing to disclose. E.C. has nothing to disclose. E.v.D.-d.B. has nothing to disclose. U.D. has nothing to disclose. H.J.v.d.P. has nothing to disclose. A.C.H.d.V. has nothing to disclose. J.F.W. has nothing to disclose. A.R. has nothing to disclose. S.D.F. has nothing to disclose. D.G. has nothing to disclose. M.M. has nothing to disclose. M.K. has nothing to disclose. T.K. has nothing to disclose. J.K. has nothing to disclose. D.M.-M. has nothing to disclose. C.S. has nothing to disclose. O.Z. has nothing to disclose. P.K. has nothing to disclose. L.C.M.K. has nothing to disclose. R.J.B. has nothing to disclose. F.W. has nothing to disclose. J.L.B. has nothing to disclose. A.G.U. has nothing to disclose. A.M.E.B. has nothing to disclose. F.E.v.L. has nothing to disclose. K.K.N. has nothing to disclose. M.M.H. has nothing to disclose. A.-L.L.F.v.d.K. has nothing to disclose. M.M.v.d.H.E. has nothing to disclose.
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