Mapping heterogeneous molecular subtypes of circadian misalignment underlying lung adenocarcinoma risk

Background: The circadian rhythm coordinates multiple physiological and behavioral processes. Substantial evidence illustrates that circadian rhythm disruption (CRD) dramatically influences tumor initiation, progression, and the tumor immune microenvironment remodeling. However, there is a dearth of exploration for CRD heterogeneity’s underlying clinical significance in lung adenocarcinoma (LUAD).Methods: 2090 LUAD patients and 79 immunotherapy patients were enrolled from nine public independent datasets. The nonnegative matrix factorization (NMF) was applied to develop molecular classification after collecting CRD-related genes. Subsequently, the reliability and robustness of classification were evaluated through the nearest template prediction (NTP) method. Furthermore, clinical outcomes, functional characteristics, genomic alterations, and immune landscape were explored. The efficacy of clinical common treatment was detected for the specific classification.Results: Three heterogeneous LUAD subtypes were identified based on the expression profile of CRD-related genes. Different expression characteristics and clinical outcomes of distinct subtypes were revealed. Relative similar clinical outcomes and proportion of each subtype were verified in multiple independent cohorts, which indicated the reliability of classification. Distinguish features of three subtypes were further explored: (i) C1, the poorest prognosis, significant cell proliferation, and highest genomic instability. (ii) C2, the best outcome, elevated lipid metabolic function, favorable regulation of circadian rhythm, and (iii) C3, copious immune infiltration, immunosuppressive microenvironment, and conspicuous intratumor heterogeneity. The evaluation of treatment strategies suggested that C1 patients might benefit from chemotherapeutics agents, including docetaxel and paclitaxel, patients in C2 were suitable for glucocorticoids, whereas C3 patients were recommended to accept immunotherapy.Conclusions: We identified three CRD subtypes with distinct characteristics, including clinical outcomes, biological function, genomic alterations, and immune landscape. For individualized subtypes, befitting therapy approaches were proposed. Our study could provide more efficient and precise management to LUAD patients.