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J Thorac Cardiovasc Surg 2008;135:627-634
© 2008 The American Association for Thoracic Surgery

General Thoracic Surgery

A simple two-gene prognostic model for adenocarcinoma of the lung

Carolyn E. Reed, MDa,*, Amanda Graham, MSa, Rana S. Hoda, MDb, Andras Khoor, MDd, Elizabeth Garrett-Mayer, PhDc, Michael B. Wallace, MDe, Michael Mitas, PhDa

a Department of Surgery, Medical University of South Carolina, Charleston, SC
b Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
c Department of Biostatics, Bioinformatics & Epidemiology, Medical University of South Carolina, Charleston, SC
d Department of Laboratory Medicine & Pathology, Mayo Clinic, Jacksonville, Fla
e Division of Gastroenterology & Hepatology, Mayo Clinic, Jacksonville, Fla

Received for publication April 23, 2007; revisions received September 3, 2007; accepted for publication October 26, 2007.

* Address for reprints: Carolyn E. Reed, MD, Medical University of South Carolina, 96 Jonathan Lucas St, 418 CSB, Charleston, SC 29425. (Email: reedce{at}musc.edu).

Objective: We hypothesized that clinical outcome of resected early-stage adenocarcinoma of the lung can be predicted by the expression of a few critically important genes as measured by quantitative real-time reverse-transcriptase polymerase chain reaction in formalin-fixed paraffin-embedded primary tumors.

Methods: Twenty-two prognostic genes for the metastatic phenotype were identified through complementary DNA microarray analysis of 4 cancer cell lines and bioinformatics analysis. Expression levels of a subset of these genes (n = 13) were measured by real-time time reverse-transcriptase polymerase chain reaction in formalin-fixed paraffin-embedded primary adenocarcinoma from patients whose disease recurred within 2 years (n = 9) and in patients who did not have a recurrence (n = 11). Receiver operating characteristic curves were analyzed to establish prognostic values of single genes. The most informative gene was combined with the remaining genes to determine whether there was a particular pair(s) that yielded high diagnostic accuracy. A small validation study was performed.

Results: Receiver operating characteristic curve analysis of the single genes revealed that high expression of CK19 was associated with nonrecurrence (area under the curve = 0.859, confidence interval = 0.651–0.970). The CK19/EpCAM2 gene ratio had the most reproducible prognostic accuracy, followed by the CK19/P-cadherin ratio. A Kaplan–Meier survival analysis generated from the CK19/EpCAM2 ratio resulted in highly significant curves as a function of marker positivity (P = .0007; hazard ratio = 10.7). Significance declined but was maintained in the validation study.

Conclusions: This preliminary study provides evidence that the CK19/EpCAM2 and/or CK19/P-cadherin ratio(s) may be a simple and accurate prognostic indicator of clinical outcome in early-stage adenocarcinoma of the lung. If further validation studies from large patient cohorts confirm the results, adjuvant therapy could be targeted to this high-risk group.

Abbreviations and Acronyms AUC = area under the curve; cDNA = complementary DNA; CI = confidence interval; cRNA = complementary RNA; Ct = cycle of threshold; NSCLC = non–small cell lung cancer; RT-PCR = reverse-transcription polymerase chain reaction


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J. Thorac. Cardiovasc. Surg. 2008 135: 633-634. [Extract] [Full Text] [PDF]





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