Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.
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Authors
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
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Bishop, DT
Reid, A
Huddart, RA
Shipley, J
Grotmol, T
Wiklund, F
Houlston, RS
Turnbull, C
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
UK Testicular Cancer Collaboration,
PRACTICAL Consortium,
Bishop, DT
Reid, A
Huddart, RA
Shipley, J
Grotmol, T
Wiklund, F
Houlston, RS
Turnbull, C
Document Type
Journal Article
Date
2017-07-01
Date Accepted
2017-05-16
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-analysis 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.
Citation
Nature genetics, 2017, 49 (7), pp. 1133 - 1140
DOI
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1061-4036
eISSN
1546-1718
Research Team
Complex Trait Genetics
Cancer Genomics
Molecular & Population Genetics
Sarcoma Molecular Pathology
Clinical Academic Radiotherapy (Huddart)
Oncogenetics
Cancer Genomics
Molecular & Population Genetics
Sarcoma Molecular Pathology
Clinical Academic Radiotherapy (Huddart)
Oncogenetics