Purpose The high 5-year disease relapse rate in patients with stage I lung adenocarcinoma indicates the need for additional risk stratification parameters. This study assessed whether gene signatures translate into a pathologic feature for better disease stratification. Materials and Methods The mutual interdependence and risk stratification power of three gene signatures, cell cycle, hypoxia, and mammalian target of rapamycin (mTOR), were investigated in nine cohorts of patients with lung adenocarcinoma and five cohorts of patients with lung squamous cell carcinoma. The translation from gene signatures to a pathologic feature, tumor necrosis, was validated in The Cancer Genome Atlas lung adenocarcinoma cohort. The translation of signature score to pathway activity was further investigated by integrative analyses using The Cancer Genome Atlas and The Cancer Protein Atlas lung adenocarcinoma data sets. Results The results showed that the three gene signatures were mutually interdependent in lung adenocarcinoma but not in lung squamous cell carcinoma. The signature activities were higher in necrosis-positive tumors than in necrosis-negative tumors. The signature score correlated with the expression level of the representative protein that implicated the activity of each pathway. These signatures stratified patients with operable and stage I lung adenocarcinomas into different risk groups independent of age and stage. Furthermore, the signatures translated to a pathologic feature, tumor necrosis, which predicted shorter overall and relapse-free survival in patients with operable and stage I lung adenocarcinomas. Conclusion This study showed that gene signatures could translate into a pathologic feature, tumor necrosis, with risk stratification ability in patients with operable and stage I lung adenocarcinomas.
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