Identification of Novel Subtypes in Lung Adenocarcinoma: Evidence from Gene Set Variation Analysis in Tumor and Adjacent Nontumor Samples

In patients with lung adenocarcinoma (LUAD), the prognostic role of adjacent nontumor tissues is still unknown. Alterations in the activity of immunologic and hallmark gene sets in adjacent nontumor tissues may have a potential influence on cell proliferation of normal lung cell after pulmonary lobectomy. We sought to discover LUAD subgroups and prognostic gene sets based on changes in gene set activity in tumor and adjacent nontumor tissues. Firstly, we used gene set variation analysis (GSVA) to characterize the activity changes of 4922 gene sets in LUAD and nontumor samples. Luckily, we identified three novel LUAD subtypes using the nonnegative matrix factorization (NMF) algorithm. In detailed, patients with subtype-3 had a favorable prognosis, but subtypes 1 and 2 had a bad prognosis. In addition, patients with subtype-3 in the validation cohort also lived longer. Meanwhile, using the LASSO-Cox algorithm, we discovered 15 prognostic gene sets in tumors (T gene sets) and two prognostic gene sets in adjacent nontumors (N gene sets). Interestingly, genes from N gene sets were related with immune response in nontumor tissues, but genes from T gene sets were correlated with DNA damaging and repairing in tumor tissues. These findings highlighted the possibility of a stronger immune response in nearby nontumor tissues. In conclusion, our study established a theoretical foundation for selecting therapy strategy for LUAD patients that should be guided by changes in activity in tumor and adjacent nontumor tissues, particularly after pulmonary lobectomy.