Abstract
We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified a previously unknown susceptibility locus for ESCC: PLCE1 at 10q23 (PHan combined for ESCC = 7.46 × 10−56, odds ratio (OR) = 1.43; PUygur-Kazakh for ESCC = 5.70 × 10−4, OR = 1.53). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma and the same 11,013 control subjects (PLCE1, PHan for GCA = 1.74 × 10−39, OR = 1.55. PLCE1 has important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis.
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Change history
27 August 2014
In contrast to the version of this article initially published, the authors now find no evidence to support association with esophageal squamous cell carcinoma susceptibility for rs13042395[T] at 20p13 in their original data, in two independent sets of cases and controls collected in other Chinese populations or in the joint analysis of these three studies. The original signal at the C20orf54 locus (rs13042395) in the published Henan genome-wide association study (GWAS) was based on the scan of a total of 2,810 subjects (1,077 cases and 1,733 controls) with a per-allele odds ratio (OR) of 0.66 (95% confidence interval (CI) = 0.58–0.74; P =1.51 × 10−11), and P < 5 × 10−6 was reported for a genetically matched subset of 937 cases and 692 controls. A new analysis by the authors (see Supplementary Table 8 in Nat. Genet. 46, 1001–1006, 2014) included a distinct genetically matched subset of the original genotypes (1,789 total subjects: 1,076 cases and 713 controls; OR = 0.80 (95% CI = 0.65–0.98); P = 0.03) and subjects scanned after publication of the initial Henan data (669 new subjects: 229 cases and 370 controls; OR = 1.06 (95% CI = 0.82–1.38); P = 0.63). The combination of the genetically matched and new subjects (n = 2,458 subjects in total: 1,375 cases and 1,083 controls) yielded OR = 0.88 (95% CI = 0.76–1.02; P = 9.12 × 10−2). Thus, the original Henan scan is the only result that showed a significant association for rs13042395. None of the three new analyses performed confirmed a significant association for rs13042395. Moreover, this SNP was not significant in the National Cancer Institute GWAS (OR = 0.95, 95% CI = 0.86–1.05; P = 3.04 × 10−1), Beijing GWAS (OR = 1.07, 95% CI = 0.93–1.23; P = 3.34 × 10−1) or combined data (OR = 0.96, 95% CI = 0.90–1.03; P = 3.02 × 10−1; see Supplementary Table 8 in Nat. Genet. 46, 1001–1006, 2014). In summary, the published association for rs13042395 did not replicate in additional analyses of data from Henan. Nor did it replicate in a GWAS from a similar high-risk population (National Cancer Institute) or in a GWAS from a low-risk population (Beijing). Thus, the original finding was likely the result of inadequate control for population stratification using the genetically unmatched subjects or, less likely, could have been due to chance alone. The error has been corrected in the HTML and PDF versions of the article. In addition, Supplementary Figures 1–4 and Supplementary Table 1 have been corrected.
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Acknowledgements
We thank all the patients and their family members whose contributions made this work possible; medical students from Xinxiang Medical University for sample and data collections; Y. Xing (Xinxiang Medical University) for organizing field work for sample collections and finding financial support for this study; the genotyping at Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, China, Hefei, Anhui for genotyping and statistical and bioinformatic analyses; B.G. Ma (Henan Provincial People's Hospital), W. Huang (Health Department of Henan Province), S.Y. Lian (Tumor Hospital of Linzhou), Z. Wang (Anyang Tumor Hospital), W. Zhang and J.T. Zhao (both People's Hospital of Heibi) for field work organization; J.H. Bian (Shantou University), J.J. Liu (Human Genetics, Genome Institute of Singapore) and I. Ding (National Cancer Institute, NIH) for discussions about the manuscript. Supported by Xinxiang Medical University Key Scientific Program (2009-5), the National Natural Science Foundations (30670956, 30971133), 863 HighTech Key Projects (2006AA02A403, 2007AA02Z161), China Key Program on Basic Research (2007CB516812), Special Scientific Programs from Science and Technology Department (2009-8), Health Department (2009-10) and Education Department (2008-7) of Henan Province and Anhui Provincial Special Scientific Program (2007-7).
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L.-D.W. and X.-J.Z. conceived of this study and obtained financial support. L.-D.W. and X.-J.Z. designed the study. Subject recruitment, biological material collection and handling along with DNA extraction in Henan, Hebei and Shanxi Provinces were supervised by L.-D.W., F.-Y.Z., Xue-Min Li and carried out by J.-L.L., X.S., Y.J., H.-L. Liu, J.-M.L., G.-Q.K., H.Q., J. Cui, L.-Q.Z., J.-Z.Y., X.-C.L., J.-L.R., Z.-C.L., W.-J.G., W.W., Y.-R.Z., W.-P.W., B.-P.C., S.-W.R., D.L., J.-W.K., Z.-M.F., S.-L.Z., Z.-G.G., X.-K.Z., N.L., Y.-H.A., F.-F.S., W.-Y.C., S.S., T.G., Jing Huang, C.Y., Jia Huang, Y. Wu, W.-B.Y., C.-W.F., H.-L. Li, L.Y., Y. Wang, J.-Y.T., Y. Lu, Y.Y., W.-L.Z., M.L., W.-J.F., X.Y., H.-J.W., S.-L.H., J. Chen, M.H., H.-Y.W., P.Z., Xiu-Min Li, J.-C.D., G.-L.X., R.W., M.G., Z.-W.C., Z.-Q.Y., Q.L., L.-Q.Y., F.-G.Z., X.-F.Y., X.-S.F., Yin Li, S.-G.G., J.-P.W., J.W., Z.-Q.B., L.G., J.-L.C., G.-C.D., X.Z., Y.-F.Z., Z.-M.D., X.-Y.J., D.-M.F., A.-F.J., J.-S.W., Q.Z., Q.-X.Z., F.-B.C., C.-D.L., J.-J.M., Z.-L.F., T.-J.L., S.-L.Q., Z.-G.C., J.-C.W., T.-Y.W. and X.H. The following authors from the various collaborating groups undertook assembly of case-control series in their respective regions and collected samples and data: I.S., F.L. and X.-M.L. in Xinjiang Uygur Autonomous Region; Q.Q. and L.-T.B. in Inner Mongolia Autonomous Region; Z.-Y.S., E.-M.L., L.-Y.X. and Z.-Y.W. in Guangdong Province; W.-K.C. in Jiangsu Province; G.-Y.L. in Shaanxi Province; Z.W. in Shandong Province; W.-J.Y. in Ningxia Hui Tribe Autonomous Region; L.-Q.C. in Sichuan Province; R.-B.L. in Fujian Province; B.L., F.-S.G., Yu Lan and Y.-J.F. in Beijing; Z.-M.C. in Guangdong Province; H.L. in Yunnan Province; S.-Q.C., W.C.Y., J.-Y.H., D.X., L.W. and Q.-P.K. participated in study design, results discussion and manuscript preparation; L.-D.S., H.-F.Z., Z.Z., X.-B.Z., X.S., G.-Q.K. and L.-Q.Z. performed the two-staged genotyping and sequencing, data manipulation, statistical and bioinformatic analyses. The manuscript was drafted by L.-D.W., and all authors contributed to the final draft.
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Wang, LD., Zhou, FY., Li, XM. et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1. Nat Genet 42, 759–763 (2010). https://doi.org/10.1038/ng.648
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DOI: https://doi.org/10.1038/ng.648
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