Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk
Menée à l'aide des données d'une méta-analyse d'association portant sur 10 156 patients atteints d'une tumeur germinale du testicule et 179 683 témoins, cette étude analyse l'association entre 273 polymorphismes à simple nucléotide de 28 gènes liés à la méthylation de l'ADN et le risque de développer la maladie
Résumé en anglais
Background: Testicular germ cell tumors (TGCTs), histologically classified as seminomas and non-seminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when are subjected to DNA methylation reprogramming. Single-nucleotide polymorphisms (SNPs) in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.
Methods: In this pathway-focused investigation we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls.
Results: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q-value ≤.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q-value=8.4x10-4), MECP2 (q-value=2x10-3) and ZBTB4 (q-value=0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q-value=2.8x10-4), but not with non-seminomatous tumors (q-value=0.22).
Conclusions: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk.
Impact: This finding suggests that TGCT pathogenesis could be associated to the folate cycle status, and this relation could be partly due to hereditary factors.
