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.
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.
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).
Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk.
This finding suggests that TGCT pathogenesis could be associated to the folate cycle status, and this relation could be partly due to hereditary factors.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jun 14 [Epub ahead of print]
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 Frone, Marija 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
University of Turin, Turin, Italy., University of Turin, Turin, Piedmont, Italy., University of Turin, Torino, Italy., University of Pennsylvania, Philadelphia, PA, United States., Perelman School of Medicine, University of Pennsylvania, United States., University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States., Rigshospitalet, Copenhagen, Denmark., University of Toronto and The Princess Margaret Cancer Centre, Canada., University of Leeds, Leeds, West Yorkshire, United Kingdom., National Cancer Institute, Bethesda, MD, United States., Fred Hutchinson Cancer Research Center, Seattle, WA, United States., University of Southern California, Los Angeles, California, United States., Technical University of Denmark, Lyngby, Denmark., USC/Norris Comprehensive Cancer Center, Los Angeles, CA, United States., University of Padova, Padova, Italy., University of Padua., National Cancer Institute, National Institutes of Health, DHHS, Rockville, MD, United States., University Hospital Centre Zagreb, Zagreb, Croatia, Croatia., University of Groningen and University Medical Center Groningen, Groningen, Netherlands., National Cancer Institute, Rockville, MD, United States., Cancer Registry of Norway, Oslo, Norway., Princess Margaret Cancer Center, University of Toronto, Toronto, Canada., OsloMet - Oslo Metropolitan University, Oslo, Norway., Harvard School of Public Health, United States., Karolinska Institutet, Stockholm, Sweden., Radboud University Medical Centre, Nijmegen, Netherlands., University Medical Center Hamburg-Eppendorf, Hamburg, Germany., città della salute e della scienza di Torino, Italy., Oslo University Hospital, Oslo, Norway., Institute of Cancer Research, London, United Kingdom., University Medical Center Groningen, University of Groningen, Groningen, Netherlands., The University of Texas MD Anderson Cancer Center, Houston, United States., Newcastle University, Newcastle, United Kingdom., Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway., Institute of Cancer Research, United Kingdom., Karolinska Institute, Stockholm, Sweden., Brown University, United States., Azienda Ospedaliera Citta' Della Salute E Della Scienza Di Torino, Turin, Italy., Fred Hutchinson Cancer Center, Seattle, WA, United States., National Cancer Institute, Rockville, Maryland, United States., Moffitt Cancer Center, Tampa, FL, United States., Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.