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

the Testicular Cancer Consortium; 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 Lesse; 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

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

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

the Testicular Cancer Consortium, 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 ForestaMegan 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 Lesse, 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

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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.

Original language	English
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	31
Issue number	9
Pages (from-to)	1769-1779
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.EPI-22-0123
Publication status	Published - 2022

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the Testicular Cancer Consortium, 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, D. T., Chanock, S. J., Chen, C., Cortessis, V. K., Dalgaard, M. D., Daneshmand, S., Ferlin, A., ... Richiardi, L. (2022). Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk. Cancer Epidemiology Biomarkers and Prevention, 31(9), 1769-1779. https://doi.org/10.1158/1055-9965.EPI-22-0123

@article{09707e63839e4268ad47bb4b157cff35,

title = "Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

doi = "10.1158/1055-9965.EPI-22-0123",

language = "English",

volume = "31",

pages = "1769--1779",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "9",

}

the Testicular Cancer Consortium, 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, Lesse, 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 2022, 'Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk', Cancer Epidemiology Biomarkers and Prevention, vol. 31, no. 9, pp. 1769-1779. https://doi.org/10.1158/1055-9965.EPI-22-0123

TY - JOUR

T1 - Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk

AU - the Testicular Cancer Consortium

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 - Lesse, 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

Y1 - 2022

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.

U2 - 10.1158/1055-9965.EPI-22-0123

DO - 10.1158/1055-9965.EPI-22-0123

M3 - Journal article

C2 - 35700037

AN - SCOPUS:85137105459

SN - 1055-9965

VL - 31

SP - 1769

EP - 1779

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 9

ER -

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

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