Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2022-09-02
Date Accepted
2022-06-06
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.
Citation
Cancer Epidemiology, Biomarkers and Prevention, 2022, pp. cebp.0123.2022-2-12 14:42:56.847 -
Source Title
Cancer Epidemiology, Biomarkers and Prevention
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1055-9965
eISSN
1538-7755
1538-7755
1538-7755
Collections
Research Team
Translational Genetics