Identification of four new susceptibility loci for testicular germ cell tumour.
Genome-wide association studies (GWAS) have identified multiple risk loci for testicular germ cell tumour (TGCT), revealing a polygenic model of disease susceptibility strongly influenced by common variation. To identify additional single-nucleotide polymorphisms (SNPs) associated with TGCT, we conducted a multistage GWAS with a combined data set of >25,000 individuals (6,059 cases and 19,094 controls). We identified new risk loci for TGCT at 3q23 (rs11705932, TFDP2, P=1.5 × 10(-9)), 11q14.1 (rs7107174, GAB2, P=9.7 × 10(-11)), 16p13.13 (rs4561483, GSPT1, P=1.6 × 10(-8)) and 16q24.2 (rs55637647, ZFPM1, P=3.4 × 10(-9)). We additionally present detailed functional analysis of these loci, identifying a statistically significant relationship between rs4561483 risk genotype and increased GSPT1 expression in TGCT patient samples. These findings provide additional support for a polygenic model of TGCT risk and further insight into the biological basis of disease development.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Kevin
K
Litchfield
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Amy
A
Holroyd
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Amy
A
Lloyd
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Peter
http://orcid.org/0000-0002-8348-5829
P
Broderick
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds LS9 7TF, UK.
Jérémie
J
Nsengimana
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.|Royal Marsden NHS Foundation Trust, London SM2 5NG, UK.
Rosalind
R
Eeles
Cancer Research UK, Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
Douglas F
DF
Easton
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Darshna
D
Dudakia
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds LS9 7TF, UK.
D Timothy
http://orcid.org/0000-0002-8752-8785
DT
Bishop
Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
Alison
A
Reid
Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
Robert A
RA
Huddart
Department of Research, Cancer Registry of Norway, 0369 Oslo, Norway.
Tom
T
Grotmol
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Fredrik
F
Wiklund
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
Janet
J
Shipley
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
Richard S
RS
Houlston
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.|William Harvey Research Institute, Queen Mary University, London EC1M 6BQ, UK.
Clare
C
Turnbull
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010454:Peptide Termination Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013736:Testicular Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C490895:GAB2 protein, human; D009687:Nuclear Proteins; D010454:Peptide Termination Factors; C094103:TFDP2 protein, human; D014157:Transcription Factors; C498432:ZFPM1 protein, human; C087971:peptide-chain-release factor 3