Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk

Chiara Grasso*, Maja Popovic, Elena Isaevska, Fulvio Lazzarato, Valentina Fiano, Daniela Zugna, John Pluta, Benita Weathers, Kurt D'Andrea, Kristian Almstrup, Lynn Anson-Cartwright, D Timothy Bishop, Stephen J Chanock, Chu Chen, Victoria K Cortessis, Marlene D Dalgaard, Siamak Daneshmand, Alberto Ferlin, Carlo Foresta, Megan N FroneMarija Gamulin, Jourik A Gietema, Mark H Greene, Tom Grotmol, Robert J Hamilton, Trine B Haugen, Russ Hauser, Robert Karlsson, Lambertus A Kiemeney, Davor Lessel, Patrizia Lista, Ragnhild A Lothe, Chey Loveday, Coby Meijer, Kevin T Nead, Jérémie Nsengimana, Rolf I Skotheim, Clare Turnbull, David J Vaughn, Fredrik Wiklund, Tongzhang Zheng, Andrea Zitella, Stephen M Schwartz, Katherine A McGlynn, Peter A Kanetsky, Katherine L Nathanson, Lorenzo Richiardi

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1769-1779
Number of pages11
Issue number9
Publication statusPublished - 1-Sept-2022

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