Dysregulation And Functional Implications Of The Circadian Clock Across Cancers

Background and objective: Circadian clock rhythm involved in the regulation of a series of important biological processes,including metabolic,immune and other related pathways.Many studies have shown that circadian clock rhythm usually plays an important role in inhibiting the occurrence and development of tumors.The purpose of this study was to systematically analyze the disorder of circadian rhythm genes in a variety of tumors through multiple sets of data from the TCGA database.Methods: Multiple groups of TCGA data were downloaded from Firehose to analyze the abnormal changes of circadian rhythm genes in tumor tissues and the differential expression of circadian rhythm genes compared with normal tissues.At the same time,based on the gene expression data of tissues,the circadian clock index was established by principal component analysis,which represented the overall level of core circadian genes,and the difference of the circadian clock index in tissues was compared.The effects of many factors,including virus,smoking and BMI,on the circadian clock index of tumor tissue were analyzed.The pathway related to the level of the circadian clock index was also analyzed by GSEA,and the relationship between the level of core circadian gene and the circadian clock index and survival was also analyzed.Results: The genomes of most of the core circadian genes(PER1/2/3,CRY1/2,CLOCK,ARNTL)were stable,and the frequency of copy number variation and mutation was less than 5%.However,the core circadian gene can be hypermethylated in DNA promoter region in most tumors,and the gene expression level is lower than that in normal tissues.The circadian clock index decreased significantly in most tumor tissues,and other factors also affected the circadian clock index.For example,the circadian clock index of hepatocellular carcinoma with HBV infection was significantly lower than that of uninfected hepatocellular carcinoma.The enrichment results showed that most of the signal transduction pathways including MAPK,JAK-STAT and immunity were also enriched in tumor samples with high circadian clock index.The circadian clock index was also positively correlated with the immunophenotype and immunophenotype score of the tumor.In addition,we found that patients with higher core circadian genes and circadian clock index indices also survived longer.Conclusion: Circadian rhythm and circadian clock gene play a very important role in tumor.Further study can promote the understanding of the role of circadian clock and circadian rhythm in tumor.