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. 2015 Oct 27:6:8690.
doi: 10.1038/ncomms9690.

Identification of four new susceptibility loci for testicular germ cell tumour

Kevin Litchfield  1 , Amy Holroyd  1 , Amy Lloyd  1 , Peter Broderick  1 , Jérémie Nsengimana  2 , Rosalind Eeles  1   3 , Douglas F Easton  4 , Darshna Dudakia  1 , D Timothy Bishop  2 , Alison Reid  5 , Robert A Huddart  5 , Tom Grotmol  6 , Fredrik Wiklund  7 , Janet Shipley  8 , Richard S Houlston  1 , Clare Turnbull  1   9
Affiliations

Identification of four new susceptibility loci for testicular germ cell tumour

Kevin Litchfield et al. Nat Commun. .

Abstract

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.

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Figures

Figure 1
Figure 1. Study design, genotyping conducted over three stages, comprising non-overlapping samples from the UK.
Imputation was performed on stage 1 GWAS data set.
Figure 2
Figure 2. Regional plots of the four new TGCT loci.
(a–d) Shown by triangles are the −log10 association P values of genotyped SNPs, based on meta-analysis (three-stage data for sentinel SNPs) and stages 1/2 for all other SNPs. Shown by circles are imputed SNPs at each locus, which were imputed from the stage 1 data set. The intensity of red shading indicates the strength of LD with the sentinel SNP (labeled). Also shown are the SNP build 37 coordinates in mega-bases (Mb), recombination rates in centi-morgans (cM) per mega-base (Mb) (in light blue) and the genes in the region (in dark blue). The zoomed-in section displays the exact LD block for each SNP, with the sentinel SNP marked with a red triangle, any significant regulatory markers denoted with a red circle and the chromHMM prediction states coloured as per the legend.
Figure 3
Figure 3. Population distribution of polygenic risk scores for TGCT, ordered from lowest to highest genetic risk (risk is relative to population median risk).
Relative risk is plotted as a blue line, lifetime risk as red bars. Values are marked for individuals in the top 1% of highest genetic risk.
See this image and copyright information in PMC

References

    1. Bray F., Ferlay J., Devesa S. S., McGlynn K. A. & Moller H. Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat. Clin. Pract. Urol. 3, 532–543 (2006). - PubMed
    1. Ruf C. G. et al. Changes in epidemiologic features of testicular germ cell cancer: age at diagnosis and relative frequency of seminoma are constantly and significantly increasing. Urol. Oncol. 32, 33 e1–33 e6 (2014). - PubMed
    1. Le Cornet C. et al. Testicular cancer incidence to rise by 25% by 2025 in Europe? Model-based predictions in 40 countries using population-based registry data. Eur. J. Cancer. 50, 831–839 (2014). - PubMed
    1. McGlynn K. A. & Cook M. B. Etiologic factors in testicular germ-cell tumors. Future Oncol. 5, 1389–1402 (2009). - PMC - PubMed
    1. Swerdlow A. J., De Stavola B. L., Swanwick M. A. & Maconochie N. E. Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 350, 1723–1728 (1997). - PubMed

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