title: Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study.
abstract: BACKGROUND
  Adequate prognostic markers to predict outcome of patients with lung cancer are still needed. The aim of this study was to assess whether choline kinase alpha (ChoKalpha) gene expression could identify patients with different prognoses. ChoKalpha is an enzyme involved in cell metabolism and proliferation and has a role in oncogene-mediated transformation in several human tumours, including lung cancer.
  
  
  METHODS
  60 patients with non-small-cell lung cancer (NSCLC) who had undergone surgical resection in a single centre were enrolled into the study as the training group. We used real-time reverse-transcriptase PCR (RT-PCR) to measure ChoKalpha gene expression and analyse the association between ChoKalpha expression and survival in evaluable patients. Additionally, a second group of 120 patients with NSCLC from a different hospital were enrolled into the study as the validation group. We did an overall analysis of all 167 patients who had available tissue to confirm the cut-off point for future studies. The primary endpoints were lung-cancer-specific survival and relapse-free survival.
  
  
  RESULTS
  Seven of the 60 patients in the training group were not evaluable due to insufficient tissue. In the 53 evaluable patients, the cut-off for those with ChoKalpha overexpression was defined by receiver operator under the curve (ROC) methodology. 4-year lung-cancer-specific survival was 54.43% (95% CI 28.24-80.61) for 25 patients with ChoKalpha expression above the ROC-defined cut-off compared with 88.27% (75.79-100) for 28 patients with concentrations of the enzyme below this cut-off (hazard ratio [HR] 3.14 [0.83-11.88], p=0.07). In the validation group, six of the 120 enrolled patients were not evaluable due to insufficient tissue. For the other 114 patients, 4-year lung-cancer-specific survival was 46.66% (32.67-59.65) for those with ChoKalpha expression above the ROC-defined cut-off compared with 67.01% (50.92-81.11) for patients with concentrations of ChoKalpha below the cut-off (HR 1.87 [1.01-3.46], p=0.04). A global analysis of all 167 patients further confirmed the association between ChoKalpha overexpression and worse clinical outcome of patients with NSCLC: 4-year lung-cancer-specific survival for ChoKalpha expression above the ROC-defined cut-off was 49.00% (36.61-60.38) compared with 70.52% (59.80-76.75) for those with concentrations of ChoKalpha below the cut-off (HR 1.98 [1.14-3.45], p=0.01). The overall analysis confirmed the cut-off for ChoKalpha expression should be 1.91-times higher than concentrations noted in healthy tissues when ChoKalpha is used as an independent predictive factor of relapse-free and lung-cancer-specific survival in patients with early-stage NSCLC.
  
  
  CONCLUSIONS
  ChoKalpha expression is a new prognostic factor that could be used to help identify patients with early-stage NSCLC who might be at high risk of recurrence, and to identify patients with favourable prognosis who could receive less aggressive treatment options or avoid adjuvant systemic treatment. New treatments that inhibit ChoKalpha expression or activity in patients with lung cancer should be studied further.
authors.affiliation: Translational Oncology Unit, CSIC-UAM-La Paz, National Center of Biotechnology, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ramírez de Molina
authors.forename: Jacinto
authors.initials: J
authors.lastname: Sarmentero-Estrada
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Belda-Iniesta
authors.forename: Miquel
authors.initials: M
authors.lastname: Tarón
authors.forename: Victor
authors.initials: V
authors.lastname: Ramírez de Molina
authors.forename: Paloma
authors.initials: P
authors.lastname: Cejas
authors.forename: Marcin
authors.initials: M
authors.lastname: Skrzypski
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.forename: Javier
authors.initials: J
authors.lastname: de Castro
authors.forename: Enrique
authors.initials: E
authors.lastname: Casado
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: García-Cabezas
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sánchez
authors.forename: Manuel
authors.initials: M
authors.lastname: Nistal
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Manuel
authors.initials: M
authors.lastname: González-Barón
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lacal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000401:mortality; D002797:Choline Kinase / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D012333:RNA, Messenger; C517212:CHKA protein, human; D002797:Choline Kinase