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Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.

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

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
2
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
3
Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
4
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, UK.
5
Tumour Profiling Unit, The Institute of Cancer Research, London, UK.
6
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
7
Division of Health Sciences, Warwick Medical School, Warwick University, Warwick, UK.
8
Institute of Population Health, University of Manchester, Manchester, UK.
9
Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
10
Royal Marsden NHS Foundation Trust, London, UK.
11
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
12
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
13
Department of Applied Health Research, University College London, London, UK.
14
Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
15
Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey, UK.
16
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
17
Cancer Registry of Norway, Oslo, Norway.
18
William Harvey Research Institute, Queen Mary University, London, UK.
19
Guys and St Thomas Foundation NHS Trust, Great Maze Pond, London, UK.

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.

PMID:
28604728
PMCID:
PMC6016736
DOI:
10.1038/ng.3896
[Indexed for MEDLINE]
Free PMC Article

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