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Lookup NU author(s): Dr Jérémie Nsengimana
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© 2022 American Association for Cancer Research. BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. 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 ≤ 0.05). 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 = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 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 = 2.8 × 10-4), but not with nonseminomatous tumors (q = 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 with the folate cycle status, and this relation could be partly due to hereditary factors.
Author(s): Grasso C, Popovic M, Isaevska E, Lazzarato F, Fiano V, Zugna D, Pluta J, Weathers B, D'Andrea K, Almstrup K, Anson-Cartwright L, Bishop DT, Chanock SJ, Chen C, Cortessis VK, Dalgaard MD, Daneshmand S, Ferlin A, Foresta C, Frone MN, Gamulin M, Gietema JA, Greene MH, Grotmol T, Hamilton RJ, Haugen TB, Hauser R, Karlsson R, Kiemeney LA, Lessel D, Lista P, Lothe RA, Loveday C, Meijer C, Nead KT, Nsengimana J, Skotheim RI, Turnbull C, Vaughn DJ, Wiklund F, Zheng T, Zitella A, Schwartz SM, McGlynn KA, Kanetsky PA, Nathanson KL, Richiardi L
Publication type: Article
Publication status: Published
Journal: Cancer Epidemiology, Biomarkers & Prevention
Year: 2022
Volume: 31
Issue: 9
Pages: 1769-1779
Print publication date: 01/09/2022
Acceptance date: 06/06/2022
ISSN (print): 1055-9965
ISSN (electronic): 1538-7755
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/1055-9965.EPI-22-0123
DOI: 10.1158/1055-9965.EPI-22-0123
PubMed id: 35700037
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