Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.
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Date
2017-07-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
UK Testicular Cancer Collaboration
PRACTICAL Consortium
Chromatin
Humans
Neoplasms, Germ Cell and Embryonal
Testicular Neoplasms
Genetic Predisposition to Disease
Risk
Gene Expression Profiling
Genotype
Polymorphism, Single Nucleotide
Adult
Middle Aged
Male
Genome-Wide Association Study
Young Adult
Molecular Sequence Annotation
Research team
Complex Trait Genetics
Cancer Genomics
Molecular & Population Genetics
Sarcoma Molecular Pathology
Clinical Academic Radiotherapy (Huddart)
Oncogenetics
Language
eng
Date accepted
2017-05-16
License start date
2017-07
Citation
Nature genetics, 2017, 49 (7), pp. 1133 - 1140
Publisher
NATURE PUBLISHING GROUP