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. 2007 Sep 20;26(43):6332-40. doi: 10.1038/sj.onc.1210461. Epub 2007 Apr 23.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Calcium-Binding Proteins
  • Cell Line, Tumor
  • Cytidine Triphosphate / analogs & derivatives
  • Cytidine Triphosphate / pharmacology
  • DNA Methylation* / drug effects
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology*
  • Humans
  • Middle Aged
  • Neoplasm Staging
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • Survival Rate
  • Time Factors


  • Calcium-Binding Proteins
  • NELL1 protein, human
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Cytidine Triphosphate
  • 5-aza-2'-deoxycytidine-5'-triphosphate
  • Azacitidine