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

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.

[1]  K. Chow,et al.  Prognosis of esophageal squamous cell carcinoma: analysis of clinicopathological and biological factors , 1999, American Journal of Gastroenterology.

[2]  U. Lehmann,et al.  Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. , 2001, Methods.

[3]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[4]  R. Nicholson,et al.  The LZT proteins; the LIV-1 subfamily of zinc transporters. , 2003, Biochimica et biophysica acta.

[5]  L. Zhang,et al.  Operable squamous esophageal cancer: Current results from the East , 1994, World Journal of Surgery.

[6]  R. Nicholson,et al.  Zinc transporter LIV-1: a link between cellular development and cancer progression , 2004, Trends in Endocrinology & Metabolism.

[7]  T. Hirano,et al.  Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer , 2004, Nature.

[8]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[9]  Lippincott-Schwartz,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S8 Table S1 Movies S1 to S3 a " Silent " Polymorphism in the Mdr1 Gene Changes Substrate Specificity Corrected 30 November 2007; See Last Page , 2022 .

[10]  K. Taylor,et al.  LIV-1 suppression inhibits HeLa cell invasion by targeting ERK1/2-Snail/Slug pathway. , 2007, Biochemical and biophysical research communications.

[11]  M. Kasuga,et al.  Favorable Genetic Polymorphisms Predictive of Clinical Outcome of Chemoradiotherapy for Stage II/III Esophageal Squamous Cell Carcinoma in Japanese , 2007, American journal of clinical oncology.

[12]  D. Radisky,et al.  Epithelial-mesenchymal transition and the stem cell phenotype. , 2008, Cell stem cell.

[13]  F. Motoi,et al.  LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. , 2009, International journal of oncology.

[14]  K. Taylor,et al.  Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach , 2009, Molecular Cancer Therapeutics.

[15]  N. Altorki,et al.  Predictors of long-term survival after resection of esophageal carcinoma with nonregional nodal metastases. , 2009, The Annals of thoracic surgery.

[16]  Y. Kamatani,et al.  Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. , 2009, Gastroenterology.

[17]  M. Beckmann,et al.  Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival. , 2010, Journal of the National Cancer Institute.

[18]  L. Butterfield,et al.  Zinc in innate and adaptive tumor immunity , 2010, Journal of Translational Medicine.

[19]  Jian-ming Wang,et al.  Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma , 2011, BMC Cancer.

[20]  Min Dai,et al.  Cancer trends in China. , 2010, Japanese journal of clinical oncology.

[21]  A. Butte,et al.  Non-Synonymous and Synonymous Coding SNPs Show Similar Likelihood and Effect Size of Human Disease Association , 2010, PloS one.

[22]  V. López,et al.  Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells. , 2010, Experimental cell research.

[23]  T. Oyama,et al.  EGFR gene alterations as a prognostic biomarker in advanced esophageal squamous cell carcinoma. , 2010, Frontiers in bioscience.

[24]  Bin Liu,et al.  Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1 , 2010, Nature Genetics.

[25]  Hongbing Shen,et al.  Genome-wide interrogation identifies YAP1 variants associated with survival of small-cell lung cancer patients. , 2010, Cancer research.

[26]  N. Hu,et al.  A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma , 2010, Nature Genetics.

[27]  A. Kuwahara,et al.  TNFRSF1B A1466G genotype is predictive of clinical efficacy after treatment with a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma , 2010, Journal of experimental & clinical cancer research : CR.

[28]  W. Dinjens,et al.  Functional Polymorphisms Associated with Disease-Free Survival in Resected Carcinoma of the Esophagus , 2010, Journal of Gastrointestinal Surgery.

[29]  N. Altorki,et al.  Predictors of survival in patients with persistent nodal metastases after preoperative chemotherapy for esophageal cancer. , 2010, The Journal of thoracic and cardiovascular surgery.

[30]  C. Kimchi-Sarfaty,et al.  Understanding the contribution of synonymous mutations to human disease , 2011, Nature Reviews Genetics.

[31]  Jian Gu,et al.  Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy. , 2011, Journal of the National Cancer Institute.

[32]  Lixin Wei,et al.  Epithelial-Mesenchymal Transition in tumor microenvironment , 2011, Cell & Bioscience.

[33]  R. Vessella,et al.  LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling , 2011, PloS one.

[34]  Yusuke Nakamura,et al.  A Genome-Wide Association Study of Overall Survival in Pancreatic Cancer Patients Treated with Gemcitabine in CALGB 80303 , 2011, Clinical Cancer Research.

[35]  Zhou Wang,et al.  Clinical study on lymph node metastatic recurrence in patients with N0 esophageal squamous cell cancer. , 2011, Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus.

[36]  Hongbing Shen,et al.  Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations , 2011, Nature Genetics.

[37]  Peter Kraft,et al.  Genome-wide association study of survival in patients with pancreatic adenocarcinoma , 2012, Gut.

[38]  N. Hayward,et al.  Helicobacter pylori infection and the risks of Barrett's oesophagus: A population‐based case–control study , 2012, International journal of cancer.

[39]  S. Natsugoe,et al.  Prognostic factors in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiation therapy , 2013, International Journal of Clinical Oncology.

[40]  R. Klein,et al.  A Replication Study and Genome-Wide Scan of Single-Nucleotide Polymorphisms Associated with Pancreatic Cancer Risk and Overall Survival , 2012, Clinical Cancer Research.

[41]  J. Liu,et al.  Which factors are associated with actual 5-year survival of oesophageal squamous cell carcinoma? , 2012, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[42]  A. Thrift,et al.  The influence of prediagnostic demographic and lifestyle factors on esophageal squamous cell carcinoma survival , 2012, International journal of cancer.

[43]  Wei Zheng,et al.  Novel genetic markers of breast cancer survival identified by a genome-wide association study. , 2012, Cancer research.

[44]  Bin Liu,et al.  : Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and , 2010 .