TY - JOUR
T1 - Association study between polymorphisms in DNA methylation-related genes and testicular germ cell tumor risk
AU - Grasso, Chiara
AU - Popovic, Maja
AU - Isaevska, Elena
AU - Lazzarato, Fulvio
AU - Fiano, Valentina
AU - Zugna, Daniela
AU - Pluta, John
AU - Weathers, Benita
AU - D'Andrea, Kurt
AU - Almstrup, Kristian
AU - Anson-Cartwright, Lynn
AU - Bishop, D Timothy
AU - Chanock, Stephen J
AU - Chen, Chu
AU - Cortessis, Victoria K
AU - Dalgaard, Marlene D
AU - Daneshmand, Siamak
AU - Ferlin, Alberto
AU - Foresta, Carlo
AU - Frone, Megan N
AU - Gamulin, Marija
AU - Gietema, Jourik A
AU - Greene, Mark H
AU - Grotmol, Tom
AU - Hamilton, Robert J
AU - Haugen, Trine B
AU - Hauser, Russ
AU - Karlsson, Robert
AU - Kiemeney, Lambertus A
AU - Lessel, Davor
AU - Lista, Patrizia
AU - Lothe, Ragnhild A
AU - Loveday, Chey
AU - Meijer, Coby
AU - Nead, Kevin T
AU - Nsengimana, Jérémie
AU - Skotheim, Rolf I
AU - Turnbull, Clare
AU - Vaughn, David J
AU - Wiklund, Fredrik
AU - Zheng, Tongzhang
AU - Zitella, Andrea
AU - Schwartz, Stephen M
AU - McGlynn, Katherine A
AU - Kanetsky, Peter A
AU - Nathanson, Katherine L
AU - Richiardi, Lorenzo
PY - 2022/9/2
Y1 - 2022/9/2
N2 - 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.
AB - 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.
KW - DNA Methylation
KW - Folic Acid
KW - Genome-Wide Association Study
KW - Humans
KW - Male
KW - Neoplasms, Germ Cell and Embryonal/genetics
KW - Polymorphism, Single Nucleotide
KW - Seminoma/genetics
KW - Testicular Neoplasms/genetics
UR - http://www.scopus.com/inward/record.url?scp=85137105459&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-22-0123
DO - 10.1158/1055-9965.EPI-22-0123
M3 - Journal article
C2 - 35700037
SN - 1055-9965
VL - 31
SP - 1769
EP - 1779
JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
IS - 9
ER -