Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

Kevin Litchfield; Max Levy; Giulia Orlando; Chey Loveday; Philip J. Law; Gabriele Migliorini; Amy Holroyd; Peter Broderick; Robert Karlsson; Trine B. Haugen; Wenche Kristiansen; Jérémie Nsengimana; Kerry Fenwick; Ioannis Assiotis; Zsofia Kote-Jarai; Alison M. Dunning; Kenneth Muir; Julian Peto; Rosalind Eeles; Douglas F Easton; Darshna Dudakia; Nick Orr; Nora Pashayan; D. Timothy Bishop; Alison Reid; Robert A. Huddart; Janet Shipley; Tom Grotmol; Fredrik Wiklund; Richard S Houlston; Clare Turnbull; UK Testicular Cancer Collaboration; The PRACTICAL Consortium

doi:10.1038/ng.3896

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

Kevin Litchfield, Max Levy, Giulia Orlando, Chey Loveday, Philip J. Law, Gabriele Migliorini, Amy Holroyd, Peter Broderick, Robert Karlsson, Trine B. Haugen, Wenche Kristiansen, Jérémie Nsengimana, Kerry Fenwick, Ioannis Assiotis, Zsofia Kote-Jarai, Alison M. Dunning, Kenneth Muir, Julian Peto, Rosalind Eeles, Douglas F EastonDarshna Dudakia, Nick Orr, Nora Pashayan, D. Timothy Bishop, Alison Reid, Robert A. Huddart, Janet Shipley, Tom Grotmol, Fredrik Wiklund, Richard S Houlston, Clare Turnbull^*, UK Testicular Cancer Collaboration, The PRACTICAL Consortium

^*Corresponding author for this work

Division of Population Health, Health Services Research & Primary Care (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

Original language	English
Pages (from-to)	1133-1140
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	7
Early online date	12 Jun 2017
DOIs	https://doi.org/10.1038/ng.3896
Publication status	Published - 2017

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https://researchonline.lshtm.ac.uk/id/eprint/3962439/

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Litchfield, K., Levy, M., Orlando, G., Loveday, C., Law, P. J., Migliorini, G., Holroyd, A., Broderick, P., Karlsson, R., Haugen, T. B., Kristiansen, W., Nsengimana, J., Fenwick, K., Assiotis, I., Kote-Jarai, Z., Dunning, A. M., Muir, K., Peto, J., Eeles, R., ... The PRACTICAL Consortium (2017). Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nature Genetics, 49(7), 1133-1140. https://doi.org/10.1038/ng.3896

@article{36a5ebd9d5904bd99bc51a1cb162bd29,

title = "Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor",

abstract = "Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.",

author = "Kevin Litchfield and Max Levy and Giulia Orlando and Chey Loveday and Law, {Philip J.} and Gabriele Migliorini and Amy Holroyd and Peter Broderick and Robert Karlsson and Haugen, {Trine B.} and Wenche Kristiansen and J{\'e}r{\'e}mie Nsengimana and Kerry Fenwick and Ioannis Assiotis and Zsofia Kote-Jarai and Dunning, {Alison M.} and Kenneth Muir and Julian Peto and Rosalind Eeles and Easton, {Douglas F} and Darshna Dudakia and Nick Orr and Nora Pashayan and Bishop, {D. Timothy} and Alison Reid and Huddart, {Robert A.} and Janet Shipley and Tom Grotmol and Fredrik Wiklund and Houlston, {Richard S} and Clare Turnbull and {UK Testicular Cancer Collaboration} and {The PRACTICAL Consortium}",

year = "2017",

doi = "10.1038/ng.3896",

language = "English",

volume = "49",

pages = "1133--1140",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Litchfield, K, Levy, M, Orlando, G, Loveday, C, Law, PJ, Migliorini, G, Holroyd, A, Broderick, P, Karlsson, R, Haugen, TB, Kristiansen, W, Nsengimana, J, Fenwick, K, Assiotis, I, Kote-Jarai, Z, Dunning, AM, Muir, K, Peto, J, Eeles, R, Easton, DF, Dudakia, D, Orr, N, Pashayan, N, Bishop, DT, Reid, A, Huddart, RA, Shipley, J, Grotmol, T, Wiklund, F, Houlston, RS, Turnbull, C, UK Testicular Cancer Collaboration & The PRACTICAL Consortium 2017, 'Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor', Nature Genetics, vol. 49, no. 7, pp. 1133-1140. https://doi.org/10.1038/ng.3896

TY - JOUR

T1 - Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

AU - Litchfield, Kevin

AU - Levy, Max

AU - Orlando, Giulia

AU - Loveday, Chey

AU - Law, Philip J.

AU - Migliorini, Gabriele

AU - Holroyd, Amy

AU - Broderick, Peter

AU - Karlsson, Robert

AU - Haugen, Trine B.

AU - Kristiansen, Wenche

AU - Nsengimana, Jérémie

AU - Fenwick, Kerry

AU - Assiotis, Ioannis

AU - Kote-Jarai, Zsofia

AU - Dunning, Alison M.

AU - Muir, Kenneth

AU - Peto, Julian

AU - Eeles, Rosalind

AU - Easton, Douglas F

AU - Dudakia, Darshna

AU - Orr, Nick

AU - Pashayan, Nora

AU - Bishop, D. Timothy

AU - Reid, Alison

AU - Huddart, Robert A.

AU - Shipley, Janet

AU - Grotmol, Tom

AU - Wiklund, Fredrik

AU - Houlston, Richard S

AU - Turnbull, Clare

AU - UK Testicular Cancer Collaboration

AU - The PRACTICAL Consortium

PY - 2017

Y1 - 2017

N2 - Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

AB - Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

U2 - 10.1038/ng.3896

DO - 10.1038/ng.3896

M3 - Article

AN - SCOPUS:85021701379

SN - 1061-4036

VL - 49

SP - 1133

EP - 1140

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

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