Hybrid models identified a 12-gene signature for lung cancer prognosis and chemoresponse prediction

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 m...

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Published inPloS one Vol. 5; no. 8; p. e12222
Main Authors Wan, Ying-Wooi, Sabbagh, Ebrahim, Raese, Rebecca, Qian, Yong, Luo, Dajie, Denvir, James, Vallyathan, Val, Castranova, Vincent, Guo, Nancy Lan
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 17.08.2010
Public Library of Science (PLoS)
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Summary: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.
Bibliography:Conceived and designed the experiments: NLG. Performed the experiments: ES RR. Analyzed the data: YWW DL JD. Contributed reagents/materials/analysis tools: YQ VV VC. Wrote the paper: YWW NLG. Guided the RT-PCR experiments: YQ. Examined lung cancer tumor tissue samples: VV.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0012222