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.
- Klíčová slova
- GWAS, Ovarian reserve, childhood cancer, gonadotoxicity, survivorship,
- MeSH
- alkylační protinádorové látky škodlivé účinky MeSH
- antimülleriánský hormon * krev genetika MeSH
- celogenomová asociační studie * MeSH
- dítě MeSH
- dospělí MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory genetika farmakoterapie MeSH
- ovariální rezerva * genetika účinky léků účinky záření MeSH
- přežívající onkologičtí pacienti * MeSH
- rizikové faktory MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Evropa epidemiologie MeSH
- Názvy látek
- alkylační protinádorové látky MeSH
- antimülleriánský hormon * MeSH
Progress in medicine has increased the survival time of children suffering from cancer; >80% of patients survive for at least 5 years from the end of treatment. However, there are late effects of anticancer therapy, which accompany this success. Two-thirds of childhood cancer survivors (CCSs) have at least one late effect (any side effects or complications of anticancer treatment that appear months to years after the completion of treatment), e.g. endocrinopathies, cardiovascular diseases or subsequent cancers, and half of these late effects are serious or life threatening. These late consequences of childhood cancer treatment pose a serious health, social and economic problem. A common mechanism for developing a number of late effects is the onset of premature biological aging, which is associated with the early onset of chronic diseases and death. Cellular senescence in cancer survivors is caused by therapy that can induce chromosomal aberrations, mutations, telomere shortening, epigenetic alterations and mitochondrial dysfunctions. The mechanisms of accelerated aging in cancer survivors have not yet been fully clarified. The measurement of biological age in survivors can help improve the understanding of aging mechanisms and identify risk factors for premature aging. However, to the best of our knowledge, no single marker for the evaluation of biological or functional age is known, so it is therefore necessary to measure the consequences of anticancer treatment using complex assessments. The present review presents an overview of premature aging in CCSs and of the mechanisms involved in its development, focusing on the association of senescence and late effects.
- Klíčová slova
- aging-related diseases, childhood cancer survivors, late effects, premature aging,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
