Increasing the understanding of the impact of changes in oncogenes and tumor suppressor genes is essential for improving the management of lung cancer. Recently, we identified a new mouse lung-specific tumor suppressor—the G protein-coupled receptor 5A (Gprc5a). Microarray analysis of the transcriptomes of lung epithelial cells cultured from normal tracheas of Gprc5a knockout and wild-type mice defined a loss-of-Gprc5a gene signature, which revealed many aberrations in cancer-associated pathways. To assess the relevance of this mouse tumor suppressor to human lung cancer, the loss-of-Gprc5a signature was cross species compared with and integrated with publicly available gene expression data of human normal lung tissue and non-small cell lung cancers. The loss-of-Gprc5a signature was prevalent in human lung adenocarcinomas compared with squamous cell carcinomas or normal lung. Furthermore, it identified subsets of lung adenocarcinomas with poor outcome. These results demonstrate that gene expression patterns of Gprc5a loss in nontumorigenic mouse lung epithelial cells are evolutionarily conserved and important in human lung adenocarcinomas.