Characteristics Of Circadian Rhythm-related Genes And Establishment Of A Prognostic Scoring System For Lung Adenocarcinoma

Objective: Non-small cell lung cancer(NSCLC)is one of the most common malignant tumors worldwide.Lung cancer is the leading cause of cancer death,accounting for 18.4% of all cancer deaths,and has the highest incidence of all types of cancer worldwide(11.6%).Lung adenocarcinoma(LUAD),the main subtype of NSCLC,has a poor prognosis.and its incidence is increasing annually.In recent years,circadian rhythm(CR)-related genes(CRRGs)have demonstrated associations with tumor occurrence and development.Many studies have shown that CRRGs regulate cell proliferation,malignant tumor cell apoptosis,and neuroendocrine and immune function.Disruption to the CR plays a key role in tumorigenesis and promotes the establishment of cancer features.Moreover,tumorigenesis impairs the CR directly.But the relationship between CRRGs and LUAD is not clear.Because of the correlation between CRRGs and tumors,we have reason to believe that CRRGs will become an important prognostic indicator for LUAD and guide the treatment of LUAD prognosis.Methods: Based on data from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases,we explored the biological function and immune cell infiltration of LUAD in different CR clusters and quantified CR genes using principal component analysis(PCA).Therefore,we established a prognostic model by univariate analysis,multivariate analysis,and principal component analysis.Then,we built a CR scoring system(CRscore).All patients in the database were divided into high score group and low score group according to the score,and the clinical characteristics(including age,sex,survival status and lung adenocarcinoma stage),tumor mutation burden(TMB),immune checkpoint,and sensitivity to chemotherapy drugs were compared between high score group and low score group.Finally,western blot analysis and quantitative real-time PCR(q RT-PCR)were used to verify the scientific validity of the scoring system.In this study,we aimed to explore the relationship between circadian rhythm-related genes(CRRGs)and prognosis of lung adenocarcinoma.And CRscore is used to guide clinical drug treatment for different patients.Results: Patients were divided into three clusters(A,B,and C).Biological characteristics,such as survival,immune cell infiltration,and gene enrichment,were significantly different among the three clusters(P<0.001).We then established the usefulness of the CR score,which could probably predict the prognosis of LUAD.Some conclusions were drawn.Patients with a high TMB and a high CR score had a longer survival time.It can be speculated that combining the CR score with the TMB can enhance the sensitivity of TMB to forecast the effectiveness of immunotherapy in patients with LUAD.Both the univariate and multivariate analyses showed that age,stage,and CR score were independent prognostic factors in this study.The expression of immune checkpoint proteins was low in patients with high CR scores and high in patients with low CR scores.Patients with high CR scores were sensitive to cisplatin,gemcitabine,paclitaxel,and vinorelbine(P<0.05),and patients with low CR scores were sensitive to methotrexate(P<0.05).These results suggest that the CRscore tool is a dependable biological index of prognostic immunotherapy and clinical efficacy.Specifically,patients with a high CR score had a better prognosis and were more sensitive to chemotherapy than those with a low CR score.Conclusions: It is possible to use CRRGs to assess the prognosis of patients with LUAD.Quantification of CR using the CRscore tool in patients with LUAD maybe help to guide personalized cancer immunotherapy strategies in the future.Thus,the CRscore may be a prognostic tool for LUAD.