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Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma

Oncogene volume 26, pages 6332–6340 (2007)Cite this article

Abstract

The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver–operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I–II (P=0.0264) but not in stages III–IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2′-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.

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References

  • Bender CM, Gonzalgo ML, Gonzales FA, Nguyen CT, Robertson KD, Jones PA . (1999). Roles of cell division and gene transcription in the methylation of CpG islands. Mol Cell Biol 19: 6690–6698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brock MV, Gou M, Akiyama Y, Muller A, Wu TT, Montgomery E et al. (2003). Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res 9: 2912–2919.

    CAS  PubMed  Google Scholar 

  • Desai J, Shannon ME, Johnson MD, Ruff DW, Hughes LA, Kerley MK et al. (2006). Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Hum Mol Genet 15: 1329–1341.

    Article  CAS  PubMed  Google Scholar 

  • Dolan K, Garde J, Gosney J, Sissons M, Wright T, Kingsnorth AN et al. (1998). Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites. Br J Cancer 78: 950–957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang MZ, Jin Z, Wang Y, Liao J, Yang GY, Wang LD et al. (2005). Promoter hypermethylation and inactivation of O(6)-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines. Int J Oncol 26: 615–622.

    CAS  PubMed  Google Scholar 

  • Gleeson CM, Sloan JM, McGuigan JA, Ritchie AJ, Weber JL, Russell SE . (1998). Barrett's oesophagus: microsatellite analysis provides evidence to support the proposed metaplasia-dysplasia-carcinoma sequence. Genes Chromosomes Cancer 21: 49–60.

    Article  CAS  PubMed  Google Scholar 

  • Hage M, Siersema PD, van Dekken H, Steyerberg EW, Dees J, Kuipers EJ. . (2004). Oesophageal cancer incidence and mortality in patients with long-segment Barrett's oesophagus after a mean follow-up of 12.7 years. Scand J Gastroenterol 39: 1175–1179.

    Article  CAS  PubMed  Google Scholar 

  • Hanley JA, McNeil BJ . (1982). The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143: 29–36.

    Article  CAS  PubMed  Google Scholar 

  • Herman JG, Baylin SB . (2003). Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: 2042–2054.

    Article  CAS  PubMed  Google Scholar 

  • Hirota WK, Loughney TM, Lazas DJ, Maydonovitch CL, Rholl V, Wong RK . (1999). Specialized intestinal metaplasia, dysplasia, and cancer of the esophagus and esophagogastric junction: prevalence and clinical data. Gastroenterology 116: 277–285.

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE . (2002). Cancer as a disease of epithelial-mesenchymal interactions and extracellular matrix regulation. Differentiation 70: 547–560.

    Article  PubMed  Google Scholar 

  • International Union against Cancer (2002). Committee on TNM Classification. TNM Classification of Malignant Tumors 6th edn. UICC: Geneva.

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). Cancer statistics, 2005. CA Cancer J Clin 55: 10–30.

    Article  PubMed  Google Scholar 

  • Kawakami K, Brabender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ et al. (2000). Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst 92: 1805–1811.

    Article  CAS  PubMed  Google Scholar 

  • Knudson AG . (2001). Two genetic hits (more or less) to cancer. Nat Rev Cancer 1: 157–162.

    Article  CAS  PubMed  Google Scholar 

  • Kuroda S, Tanizawa K . (1999). Involvement of epidermal growth factor-like domain of NELL proteins in the novel protein-protein interaction with protein kinase C. Biochem Biophys Res Commun 265: 752–757.

    Article  CAS  PubMed  Google Scholar 

  • Lee EJ, Lee BB, Kim JW, Shim YM, Hoseok I, Han J et al. (2006). Aberrant methylation of Fragile Histidine Triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma. Eur J Cancer 42: 972–980.

    Article  CAS  PubMed  Google Scholar 

  • Lemaire M, Momparler LF, Bernstein ML, Marquez VE, Momparler RL . (2005). Enhancement of antineoplastic action of 5-aza-2′-deoxycytidine by zebularine on L1210 leukemia. Anticancer Drugs 16: 301–308.

    Article  CAS  PubMed  Google Scholar 

  • Matsuhashi S, Noji S, Koyama E, Myokai F, Ohuchi H, Taniguchi S et al. (1995). New gene, nel, encoding a M(r) 93 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos. Dev Dyn 203: 212–222.

    Article  CAS  PubMed  Google Scholar 

  • Matsuhashi S, Noji S, Koyama E, Myokai F, Ohuchi H, Taniguchi S et al. (1996). New gene, nel, encoding a Mr 91 K protein with EGF-like repeats is strongly expressed in neural tissues of early stage chick embryos. Dev Dyn 207: 233–234.

    Article  CAS  PubMed  Google Scholar 

  • Momparler RL . (2005). Epigenetic therapy of cancer with 5-aza-2′-deoxycytidine (decitabine). Semin Oncol 32: 443–451.

    Article  CAS  PubMed  Google Scholar 

  • Mori Y, Cai K, Cheng Y, Wang S, Paun B, Hamilton JP et al. (2006). A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer. Gastroenterology 131: 797–808.

    Article  CAS  PubMed  Google Scholar 

  • Rowinsky EK . (2005). Targeted induction of apoptosis in cancer management: the emerging role of tumor necrosis factor-related apoptosis-inducing ligand receptor activating agents. J Clin Oncol 23: 9394–9407.

    Article  CAS  PubMed  Google Scholar 

  • Rudolph RE, Vaughan TL, Storer BE, Haggitt RC, Rabinovitch PS, Levine DS et al. (2000). Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus. Ann Intern Med 132: 612–620.

    Article  CAS  PubMed  Google Scholar 

  • Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y et al. (2005). Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene 24: 4138–4148.

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Morales TG, Bhattacharyya A, Garewal HS, Sampliner RE . (1997). Dysplasia in short-segment Barrett's esophagus: a prospective 3-year follow-up. Am J Gastroenterol 92: 2012–2016.

    CAS  PubMed  Google Scholar 

  • Shibata DM, Sato F, Mori Y, Perry K, Yin J, Wang S et al. (2002). Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. Cancer Res 62: 5637–5640.

    CAS  PubMed  Google Scholar 

  • Stewart BW, Kleihues P, International Agency for Research on Cancer. (2003). World Cancer Report. IARC Press: Lyon.

    Google Scholar 

  • Watanabe TK, Katagiri T, Suzuki M, Shimizu F, Fujiwara T, Kanemoto N et al. (1996). Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 38: 273–276.

    Article  CAS  PubMed  Google Scholar 

  • Weston AP, Krmpotich PT, Cherian R, Dixon A, Topalosvki M. . (1997). Prospective long-term endoscopic and histological follow-up of short segment Barrett's esophagus: comparison with traditional long segment Barrett's esophagus. Am J Gastroenterol 92: 407–413.

    CAS  PubMed  Google Scholar 

  • Zhang X, Carpenter D, Bokui N, Soo C, Miao S, Truong T et al. (2003). Overexpression of Nell-1, a craniosynostosis-associated gene, induces apoptosis in osteoblasts during craniofacial development. J Bone Miner Res 18: 2126–2134.

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Cowan CM, Jiang X, Soo C, Miao S, Carpenter D et al. (2006). Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development. Lab Invest 86: 633–644.

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Kuroda S, Carpenter D, Nishimura I, Soo C, Moats R et al. (2002). Craniosynostosis in transgenic mice overexpressing Nell-1. J Clin Invest 110: 861–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Yutaka Shimada for his generous gift of excellent cell lines. This work was supported by NIH grants CA085069, CA001808 and CA106763 to SJ Meltzer.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Z Jin, Y Mori, J Yang, F Sato, T Ito, Y Cheng, B Paun, J P Hamilton, T Kan, A Olaru, S David, R Agarwal, J M Abraham & S J Meltzer

  2. Division of General Thoracic Surgery, Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA

    D Beer

  3. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    E Montgomery

  4. Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    S J Meltzer

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  1. Z Jin
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Correspondence to S J Meltzer.

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Jin, Z., Mori, Y., Yang, J. et al. Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene 26, 6332–6340 (2007). https://doi.org/10.1038/sj.onc.1210461

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