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

被引：96

作者：

Litchfield, Kevin ^{[1
]}

Levy, Max ^{[1
]}

Orlando, Giulia ^{[1
]}

Loveday, Chey ^{[1
]}

Law, Philip J. ^{[1
]}

Migliorini, Gabriele ^{[1
]}

Holroyd, Amy ^{[1
]}

Broderick, Peter ^{[1
]}

Karlsson, Robert ^{[2
]}

Haugen, Trine B. ^{[3
,4
]}

Kristiansen, Wenche ^{[3
,4
]}

Nsengimana, Jeremie ^{[5
]}

Fenwick, Kerry ^{[6
]}

Assiotis, Ioannis ^{[6
]}

Kote-Jarai, ZSofia ^{[1
]}

Dunning, Alison M. ^{[7
]}

Muir, Kenneth ^{[8
,9
]}

Peto, Julian ^{[10
]}

Eeles, Rosalind ^{[1
,11
]}

Easton, Douglas F. ^{[12
]}

Dudakia, Darshna ^{[1
]}

Orr, Nick ^{[13
]}

Pashayan, Nora ^{[14
]}

Bishop, D. Timothy

Reid, Alison ^{[15
]}

Huddart, Robert A. ^{[16
]}

Shipley, Janet ^{[17
]}

Grotmol, Tom ^{[18
]}

Wiklund, Fredrik ^{[2
]}

Houlston, Richard S. ^{[1
]}

Turnbull, Clare ^{[1
,19
,20
]}

机构：

[1] Inst Canc Res, Div Genet & Epidemiol, London, England

[2] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[3] Fac Hlth Sci, Oslo, Norway

[4] Akershus Univ, Coll Appl Sci, Oslo, Norway

[5] Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds, W Yorkshire, England

[6] Inst Canc Res, Tumour Profiling Unit, London, England

[7] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[8] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Warwick, England

[9] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England

[10] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England

[11] Royal Marsden NHS Fdn Trust, London, England

[12] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[13] Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England

[14] UCL, Dept Appl Hlth Res, London, England

[15] Royal Marsden NHS Fdn Trust, Acad Urooncol Unit, Sutton, Surrey, England

[16] Inst Canc Res, Acad Radiotherapy Unit, Sutton, Surrey, England

[17] Inst Canc Res, Div Mol Pathol, London, England

[18] Canc Registry Norway, Oslo, Norway

[19] Queen Mary Univ, William Harvey Res Inst, London, England

[20] Guys & St Thomas Fdn NHS Trust, London, England

来源：

NATURE GENETICS | 2017年 / 49卷 / 07期

基金：

美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; CANCER-RISK; GENOTYPE IMPUTATION; BREAST-CANCER; CHROMATIN; VARIANTS; PROTEIN; SPECIFICATION; CONSERVATION; METAANALYSIS;

D O I：

10.1038/ng.3896

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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(1). 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.

引用

页码：1133 / +

页数：11

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