Elsevier

The Lancet Oncology

Volume 8, Issue 10, October 2007, Pages 889-897
The Lancet Oncology

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Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study

https://doi.org/10.1016/S1470-2045(07)70279-6Get rights and content

Summary

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 (ChoKα) gene expression could identify patients with different prognoses. ChoKα 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 ChoKα gene expression and analyse the association between ChoKα 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.

Findings

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 ChoKα 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 ChoKα 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 ChoKα expression above the ROC-defined cut-off compared with 67·01% (50·92–81·11) for patients with concentrations of ChoKα 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 ChoKα overexpression and worse clinical outcome of patients with NSCLC: 4-year lung-cancer-specific survival for ChoKα 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 ChoKα below the cut-off (HR 1·98 [1·14–3·45], p=0·01). The overall analysis confirmed the cut-off for ChoKα expression should be 1·91-times higher than concentrations noted in healthy tissues when ChoKα is used as an independent predictive factor of relapse-free and lung-cancer-specific survival in patients with early-stage NSCLC.

Interpretation

ChoKα 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 ChoKα expression or activity in patients with lung cancer should be studied further.

Introduction

Lung cancer is the leading cause of cancer-related death, accounting for one-third of all deaths from cancer worldwide.1 Lung cancer consists of a number of diseases of diverse aetiology, divided broadly into small-cell lung cancer (SCLC), which comprises 20% of all lung cancers, and non-small-cell lung cancer (NSCLC), which accounts for the remaining 80%.2 NSCLC is thought to originate in lung epithelial cells and includes diverse histological subtypes, including adenocarcinoma, bronchioloalveolar, squamous, anaplastic and large-cell carcinoma.2 Despite intensive research over the past decades, 5-year survival of patients with lung cancer is less than 15%.3 Currently, the most accurate prognostic factor for patients with NSCLC is tumour, node, metastasis (TNM) staging.3, 4 However, patients with early-stage NSCLC have a broad spectrum of survival, which indicates the need for additional prognostic parameters to better predict disease outcome.3 In the past decade, efforts have focused on the identification of molecular markers that could identify patients with a high risk of relapse after curative surgical resection.5

To improve global survival, several immunohistochemical markers have been proposed as prognostic indicators, including KRAS, P53, PRb, Ki-67, and the excision repair cross-complementation protein ERCC1.6, 7, 8, 9 Additionally, other molecules, such as cyclooxygenase-2, E-cadherin, vascular endothelial growth factor (VEGF), and epidermal-growth-factor receptor (EGFR), have been analysed at the mRNA level for their prognostic usefulness.10, 11, 12 These developments validate the use of techniques based on mRNA measurements as useful and highly reproducible methods for the classification and prognosis of various types of cancers.13, 14, 15, 16 However, given that the 5-year overall survival of patients with lung cancer is still poor, a better understanding of the molecular biology of tumours, new biological prognostic markers, and new approaches for treatment are still needed to improve clinical diagnosis, therapeutic treatment and, consequently, patient outcome.

Choline kinase alpha (ChoKα), the enzyme responsible for the generation of phosphorylcholine, is involved in metabolic processes and cell proliferation.17, 18 Studies have shown a role for ChoKα in oncogene-mediated transformation19, 20 and in the generation of human tumours, including lung cancer.21, 22, 23, 24, 25 Also, ChoKα has been described as a new oncogene that mediates human cell transformation and induces in-vivo tumorigenesis.26 Furthermore, ChoKα-specific inhibitors have been shown to have in-vitro antiproliferative and in-vivo antitumoral activity against human xenografts.27, 28, 29, 30, 31, 32

In this study, we aimed to assess whether ChoKα gene expression could identify patients with different prognoses.

Section snippets

Patients

60 patients were enrolled initially in the training group and we analysed frozen specimens of cancer tissue from 53 patients for whom we had tissue, who had NSCLC, and who had undergone surgical resection for NSCLC between February, 2001, and December, 2004, and who were followed up by the Medical Oncology Division at La Paz University Hospital, Madrid, Spain. Inclusion criteria were: age 18 years or older; completely resected NSCLC; intraoperative mediastinal-node dissection for reliable

Results

ChoKα expression and activity were first established in different cell lines derived from human lung cancer. ChoKα mRNA levels, in terms of their corresponding normal human primary BEC, were increased in all the tumour cell lines analysed in this study (figure 1). The noted increase in mRNA levels resulted in an increase in protein expression and ChoK enzymatic activity (figure 1). Therefore, protein concentrations and enzymatic activity correlated well with mRNA concentrations. These results

Discussion

In our study, an overall analysis of the training and validation groups showed that patients with NSCLC who had ChoKα overexpression had worse survival than those without overexpression. We also noted that the cut-off point for ChoKα expression should be 1·91-times higher than concentrations noted in healthy tissues.

We used different human cell lines from patients with NSCLC to analyse ChoKα expression and assess the correlation between mRNA levels, protein expression, and enzymatic activity of

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