Abstract
We conducted a genome-wide scan of SNPs to identify variants associated with length of survival in 1,331 individuals with esophageal squamous-cell carcinoma (ESCC), with associations validated in 2 independent sets including 1,962 individuals with this cancer. We identified rs1050631 in SLC39A6 as associated with the survival times of affected individuals, with the hazard ratio for death from ESCC in the combined sample being 1.30 (95% confidence interval (CI) = 1.19−1.43; P = 3.77 × 10−8). rs7242481, located in the 5′ UTR of SLC39A6, disturbs a transcriptional repressor binding site and results in upregulation of SLC39A6 expression. Immunohistochemical staining of ESCC tissues showed that higher expression of SLC39A6 protein was correlated with shorter length of survival in individuals with advanced ESCC (P = 0.013). Knockdown of SLC39A6 expression suppressed proliferation and invasion in ESCC cells. These results suggest that SLC39A6 has an important role in the prognosis of ESCC and may be a potential therapeutic target.
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Acknowledgements
We acknowledge Y. Shimada (Hyogo College of Medicine) for providing the eight ESCC cell lines. This work was funded by the National Basic Research Program of China (2013CB910303 and 2011CB504303) and the National Natural Science Foundation of China (91229126).
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Dongxin Lin was the overall principal investigator of the study who conceived the study, obtained financial support, was responsible for study design, oversaw the entire study, interpreted the results, and wrote parts of and synthesized the manuscript. C.W. performed overall project management, oversaw laboratory analyses, performed statistical analyses and drafted the initial version of the manuscript. D. Li, Y.Q., Yuling Zhou, J.C., K.Z. and Menghan Wang performed functional analyses. W.J. and Y. Zeng were responsible for subject recruitment and sample preparation for Guangzhou samples. Z.H., Yifeng Zhou and H.S. were responsible for subject recruitment and sample preparation for Jiangsu samples. D.Y. and W.T. performed subject recruitment and sample preparation for Beijing samples. T.T. and Mingrong Wang were responsible for subject recruitment and preparation of ESCC tissue microarrays. Dongmei Lin and L.W. were responsible for the IHC analysis of tissue microarrays.
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Supplementary Text and Figures
Supplementary Tables 1 and 3, Supplementary Figures 1–6 (PDF 1212 kb)
Supplementary Table 2
Associations of SNPs in SLC39A6 region with hazard risk of death of ESCC patients in the discovery sample (XLSX 13 kb)
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Wu, C., Li, D., Jia, W. et al. Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma. Nat Genet 45, 632–638 (2013). https://doi.org/10.1038/ng.2638
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DOI: https://doi.org/10.1038/ng.2638
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