ESPEYB25 9. Oncology and Chronic Disease Fertility Issues (3 abstracts)
FertilSteril. 2024 Sep;122(3):514-524. PMID: 38729340. doi: 10.1016/j.fertnstert.2024.05.002. [email protected]
Brief summary: This genome-wide association study (GWAS) identified genetic polymorphisms related to increased risk of gonadotoxicity in cancer survivors (CSs), in data from 2 independent CSs cohorts.
The analysis was conducted in 743 patients of the pan-European PanCareLIFE cohort and in 391 of US-based St. Jude Lifetime Cohort (SJLIFE). Since the aim was to identify genetic variants that may explain treatment-related interindividual variability, childhood cancer survivors whose gonadal function was unlikely to be further influenced by genetic variability were excluded. This group included survivors who had received bilateral ovarian irradiation (defined as bilateral irradiation of the abdomen below the pelvic/iliac crest), central nervous system or total body irradiation, as well as those who underwent bilateral oophorectomy or hematopoietic stem cell transplantation.
Three genome-wide significant and 16 genome-wide suggestive loci were associated with anti-Müllerian hormone (AMH) levels, adjusted for cyclophosphamide equivalent dose, age at diagnosis, and age at the study. On the basis of the effect allele frequency and biologic relevance, 15 single nucleotide polymorphisms (SNP) were selected for replication. None of the single SNPs were statistically significantly associated with AMH levels. To identify potential clinical significance of the variants detected, the authors performed a meta-analysis of the results and found that one SNP located on chromosome 1 (rs78861946) showed a borderline genome-wide significance. This revealed a potential association with gonadal damage, expressed as reduction of AMH levels, in CSs treated with high dose of alkylating agents. It is noteworthy that this variant is located in the intronic region of the RGS5 gene, close to RSG4 and NUF2 genes, involved in FSH receptor signalling, cell cycle regulation, follicular atresia and apoptosis, which are underlying mechanisms of natural menopause.
Comment: The increased survival rates after cancer have led to greater attention to gonadotoxic effects and impaired fertility, clarifying specific risk factors such as the use of alkylating agents and/or ovarian radiotherapy, as well as predictors like AMH. Given that age at menopause is influenced by genetic factors in the general population, some studies have been conducted in CSs to identify a genetic basis for the observed variability in premature menopause or likelihood of pregnancy in CSs. This study represents the first application of GWAS to identify polymorphisms associated with reduced ovarian reserve in CSs, involving the comparison of two independent cohorts to assess the reproducibility of the findings. GWAS could represent a valuable tool to find genetic markers to early identify patients needing a closer follow up and accurate support for an increased risk of ovarian damage.