Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

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

Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2022;31(9):1769-1779

PMID: 35700037

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Abstract

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.

Address: Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO Piedmont, Turin, Italy.; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.; Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Surgery (Urology), University of Toronto and The Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Department of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.; Division of Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.; Program in Epidemiology, Fred Hutchinson Cancer Center, Seattle, Washington.; Department of Epidemiology, University of Washington, Seattle, Washington.; Department of Population and Public Health Sciences, and Obstetrics and Gynecology, Keck School of Medicine at the University of Southern California, Los Angeles, California.; Department of Health Technology, Technical University of Denmark, Lyngby, Denmark.; Department of Urology, Keck School of Medicine at the University of Southern California, Los Angeles, California.; Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, Padova, Italy.; Department of Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.; Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.; Department of Research, Cancer Registry of Norway, Oslo, Norway.; Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway.; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Radboud University Medical Center, Nijmegen, the Netherlands.; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Division of Medical Oncology, AOU "Città della Salute e della Scienza di Torino", Turin, Italy.; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.; Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.; Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom.; Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.; Royal Marsden NHS Foundation Hospital, London, United Kingdom.; Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Cancer Center, Perelman School of Medicine, Philadelphia, Pennsylvania.; Department of Epidemiology, Brown School of Public Health, Brown University, Providence, Rhode Island.; Division of Urology, Department of Surgical Science, AOU "Città della Salute e della Scienza di Torino", University of Turin, Turin, Italy.; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

DOI: 10.1158/1055-9965.EPI-22-0123

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MeSH Terms: DNA Methylation, Folic Acid, Genome-Wide Association Study, Humans, Male, Neoplasms, Germ Cell and Embryonal, Polymorphism, Single Nucleotide, Seminoma, Testicular Neoplasms