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Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma

Nature Genetics volume 45, pages 632–638 (2013)Cite this article

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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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Figure 1: Kaplan-Meier estimates of survival time for individuals with ESCC stratified by SLC39A6 genotype.
Figure 2: Functional characterization of the rs7242481 SNP.
Figure 3: Expression of SLC39A6 in human ESCC cell lines and clinical specimens.
Figure 4: Effects of SLC39A6 knockdown on ESCC cell proliferation, migration and invasion.

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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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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Chen Wu, Dong Li, Dianke Yu, Tong Tong, Mingrong Wang, Yan Qiao, Yuling Zhou, Jiang Chang, Kan Zhai, Menghan Wang, Lixuan Wei, Wen Tan & Dongxin Lin

  2. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Chen Wu, Dianke Yu, Jiang Chang, Wen Tan & Dongxin Lin

  3. State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Weihua Jia & Yixin Zeng

  4. Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China

    Zhibin Hu & Hongbing Shen

  5. Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China

    Yifeng Zhou

  6. Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

    Dongmei Lin

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Contributions

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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Correspondence to Dongxin Lin.

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Supplementary information

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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