School of Medicine
Lung cancer remains the leading cause of cancer-related deaths worldwide. The recurrence rate ranges from 35–50% among early stage non-small cell lung cancer patients. To date, there is no fully-validated and clinically applied prognostic gene signature for personalized treatment.
From genome-wide mRNA expression profiles generated on 256 lung adenocarcinoma patients, a 12-gene signature was identified using combinatorial gene selection methods, and a risk score algorithm was developed with Naïve Bayes. The 12-gene model generates significant patient stratification in the training cohort HLM & UM (n = 256; log-rank P = 6.96e-7) and two independent validation sets, MSK (n = 104; log-rank P = 9.88e-4) and DFCI (n = 82; log-rank P = 2.57e-4), using Kaplan-Meier analyses. This gene signature also stratifies stage I and IB lung adenocarcinoma patients into two distinct survival groups (log-rank P<0.04). The 12-gene risk score is more significant (hazard ratio = 4.19, 95% CI: [2.08, 8.46]) than other commonly used clinical factors except tumor stage (III vs. I) in multivariate Cox analyses. The 12-gene model is more accurate than previously published lung cancer gene signatures on the same datasets. Furthermore, this signature accurately predicts chemoresistance/chemosensitivity to Cisplatin, Carboplatin, Paclitaxel, Etoposide, Erlotinib, and Gefitinib in NCI-60 cancer cell lines (P<0.017). The identified 12 genes exhibit curated interactions with major lung cancer signaling hallmarks in functional pathway analysis. The expression patterns of the signature genes have been confirmed in RT-PCR analyses of independent tumor samples.
The results demonstrate the clinical utility of the identified gene signature in prognostic categorization. With this 12-gene risk score algorithm, early stage patients at high risk for tumor recurrence could be identified for adjuvant chemotherapy; whereas stage I and II patients at low risk could be spared the toxic side effects of chemotherapeutic drugs.
Digital Commons Citation
Wan, Ying-Wooi; Sabbagh, Ebrahim; Raese, Rebecca; Qian, Yong; Luo, Dajie; Denvir, James; Vallyathan, Val; and Castranova, Vincent, "Hybrid Models Identified a 12-Gene Signature for Lung Cancer Prognosis and Chemoresponse Prediction" (2010). Faculty & Staff Scholarship. 2757.
Wan Y-W, Sabbagh E, Raese R, Qian Y, Luo D, Denvir J, et al. (2010) Hybrid Models Identified a 12-Gene Signature for Lung Cancer Prognosis and Chemoresponse Prediction. PLoS ONE 5(8): e12222. https://doi.org/10.1371/journal.pone.0012222