Cancer Epidemiol Biomarkers Prev. 2022 Jun 14:cebp.0123.2022-2-12 14:42:56.847. doi: 10.1158/1055-9965.EPI-22-0123. Online ahead of print.
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=8.4×10-4), MECP2 (q-value=2×10-3) 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=2.8×10-4), 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.