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

Authors
Wan-YW; Sabbagh-E; Raese-R; Qian-Y; Luo-D; Denvir-J; Vallyathan-V; Castranova-V; Guo-NL
Source
PLoS One 2010 Aug; 5(8):e12222
NIOSHTIC No.
20037340
Abstract
Background: 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. Methodology/Principal Findings: 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 Na´ve 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. Conclusions/Significance: 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.
Keywords
Genetic-engineering; Genetics; Genes; Cancer; Lung-cancer; Lung-disease; Lung-disorders; Respiratory-system-disorders; Humans; Biomarkers; Chemotherapy; Medical-research; Medical-treatment; Medicinal-chemicals
CODEN
POLNCL
CAS No.
33069-62-4; 15663-27-1
Publication Date
20100817
Document Type
Journal Article
Email Address
lguo@hsc.wvu.edu
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Issue of Publication
8
ISSN
1932-6203
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Public Library of Science One
State
WV
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