A 4-gene signature predicts survival of patients with resected adenocarcinoma of the esophagus, junction, and gastric cardia

Gastroenterology. 2010 Dec;139(6):1995-2004.e15. doi: 10.1053/j.gastro.2010.05.080. Epub 2010 Jun 2.


Background & aims: The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the past 30 years and 5-year survival remains approximately 20%. Current staging is limited in its ability to predict survival which has ramifications for treatment choices. The aim of this study was to generate and validate a molecular prognostic signature for esophageal adenocarcinoma.

Methods: Gene expression profiling was performed and the resulting 42,000 gene signatures correlated with clinical and pathologic features for 75 snap-frozen esophageal and junctional resection specimens. External validation of selected targets was performed on 371 independent cases using immunohistochemistry to maximize clinical applicability.

Results: A total of 119 genes were associated significantly with survival and 270 genes with the number of involved lymph nodes. Filtering of these lists resulted in a shortlist of 10 genes taken forward to validation. Four genes proved to be prognostic at the protein level (deoxycytidine kinase [DCK], 3'-phosphoadenosine 5'-phosphosulfate synthase 2 [PAPSS2], sirtuin 2 [SIRT2], and tripartite motif-containing 44 [TRIM44]) and were combined to create a molecular prognostic signature. This 4-gene signature was highly predictive of survival in the independent external validation cohort (0/4 genes dysregulated 5-year survival, 58%; 95% confidence interval [CI], 36%-80%; 1-2/4 genes dysregulated 5-year survival, 26%; 95% CI, 20%-32%; and 3-4/4 genes dysregulated 5-year survival, 14%; 95% CI, 4%-24% (P = .001). Furthermore, this 4-gene signature was independently prognostic in a multivariable model together with the existing clinical TNM staging system (P = .013).

Conclusions: This study has generated a clinically applicable prognostic gene signature that independently predicts survival in an external validation cohort and may inform management decisions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / mortality
  • Adenocarcinoma* / surgery
  • Adult
  • Aged
  • Aged, 80 and over
  • Cardia / surgery
  • Esophageal Neoplasms* / genetics
  • Esophageal Neoplasms* / mortality
  • Esophageal Neoplasms* / surgery
  • Esophagogastric Junction / surgery
  • Esophagus / surgery
  • Female
  • Gene Expression Profiling / standards*
  • Gene Expression Regulation, Neoplastic
  • Genetic Markers*
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Prognosis
  • Reproducibility of Results
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / mortality
  • Stomach Neoplasms* / surgery


  • Genetic Markers