Development of a RNA-Seq Based Prognostic Signature for Lung Cancer

Precision therapy for lung cancer will require comprehensive genomic testing to identify actionable targets as well as ascertain disease prognosis. RNA-seq is a robust platform that meets these requirements, but microarray-derived prognostic signatures are not optimal for RNA-seq data. Thus, University of Michigan researchers undertook the first prognostic analysis of lung adenocarcinoma RNA-seq data and generated a prognostic signature.

Lung adenocarcinoma RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) were divided chronologically into training (n = 255) and validation (n = 157) cohorts. In the training cohort, prognostic association was assessed by univariate Cox analysis. A prognostic signature was built with stepwise multivariable Cox analysis. Outcomes by risk group, stage, and mutation status were analyzed with Kaplan-Meier and multivariable Cox analyses. All the statistical tests were two-sided.

In the training cohort, 96 genes had prognostic association with P values of less than or equal to 1.00×10-4, including five long noncoding RNAs (lncRNAs). Stepwise regression generated a four-gene signature, including one lncRNA. Signature high-risk cases had worse overall survival (OS) in the TCGA validation cohort and a University of Michigan institutional cohort, and worse metastasis-free survival in the TCGA validation cohort. The four-gene prognostic signature also statistically significantly stratified overall survival in important clinical subsets, including stage, EGFR wild-type, and EGFR mutant. The four-gene prognostic signature also stood out on top when compared with other prognostic signatures.

Identification of prognostic gene signature


A) RNA-seq prognostic analysis and signature generation pipeline. B) Oncomine lung adenocarcinoma signature concept analysis of top 96 prognostic genes.

Shukla S, Evans JR, Malik R, Feng FY, Dhanasekaran SM, Cao X, Chen G, Beer DG, Jiang H, Chinnaiyan AM. (2016) Development of a RNA-Seq Based Prognostic Signature in Lung Adenocarcinoma. J Natl Cancer Inst 109(1). [abstract]

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