The Aberrant Expression Of Rhythm Genes In Pan-cancer And Its Effect On Genome Instability And Tumor Immunity

Background and purpose Rhythm genes are a group of genes that are expressed periodically over a24-hour period.Rhythm genes not only control the circadian rhythm,but also regulate various physiological functions and behavioral abilities of the organisms.Changes in the expression of rhythm genes can cause the occurrence and development of tumors.Although studies have shown that certain rhythm genes regulate the progression of cancers,the expression and roles of the vast majority of rhythm genes in human cancers are largely unknown.Therefore,the main purpose of this study is to analyze the abnormal expression of rhythm genes in pan-cancer and explore the hallmarks of cancer that may be affected by the abnormal expression of rhythm genes.Methods In this study,32 rhythm genes were identified by searching the gene database and related literatures.Then,mutation data of 32 rhythm genes in 31 kinds of malignant tumors were collected from the c Bio Portal database.The mutation of rhythm genes was analyzed by R package ggplot2 of R3.6.1.The t test was used to analyze the difference in the expression of rhythm genes between malignant and normal tissues,and Pearson correlation analysis method was used to analyze the correlation between the expression of rhythm genes and promoter methylation level in pan-cancer.The Ch IP-seq database was used to detect the transcriptional regulation of12 rhythm genes as transcription factors on other rhythm genes in different types of malignant tumors.The hypergeometric test was used to analyze which cancer hallmarks were regulated by rhythm genes.The correlation between the expression of rhythm genes and tumor mutation burden(TMB)was further analyzed by Pearson correlation analysis method,as well as the correlation between rhythm genes and the levels of different types of immune cell infiltration in tumor tissues.In addition,the GEPIA2 database was used to analyze the expression of 32 rhythm genes in 33 malignant tumors and their relationship with patient survival,and Cox proportional risk regression model was used for survival analysis.Finally,based on published data sets,t test was used to analyze the relationship between the expression of rhythmic genes and the efficacy of anti-PD-1 therapy,anti-CTLA4 therapy,and their combined immunotherapy.Results We found that most of the rhythm genes have high frequency mutations in pan-cancer,suggesting that the rhythm genes may be related to the occurrence and development of cancer.Cluster analysis showed that the expression of rhythm genes was significantly abnormal in pan-cancer,and the expression level of most rhythm genes was negatively correlated with the methylation level of their promoters,suggesting that the expression of rhythm gene may be related to the methylation status of the gene.Analysis of Cistrome DB data showed that some rhythm genes could be used as transcription factors to regulate the expression of other rhythm genes in different types of malignant tumors,and some rhythm genes could also regulate their own transcription.The hypergeometric test showed that rhythm genes were significantly associated with genome instability.In most cancer types,the expression of certain rhythm genes was related to tumor mutation burden,microsatellite instability(MSI)and the expression of DNA damage repair genes.Using the Pearson correlation analysis method,it was found that the rhythm gene was also related to the level of immune cell infiltration in the tumor microenvironment.The Cox proportional hazards regression model found that the expression level of certain rhythm genes was associated with prognosis of cancer patients.In addition,differential expression of certain rhythm genes in many cancer patients has been found to be closely related to the efficacy of immune checkpoint blocking therapy.Conclusions In this study,a series of statistical and bioinformatics methods were used to identify high-frequency mutations and aberrant expression of rhythm genes in pan-cancer,and the expression level of most rhythm genes was negatively correlated with the methylation level of their promoters.Some rhythm genes regulate the expression of other rhythm genes or themselves by functioning as a transcription factor in various cancer types.Rhythm genes were involved in regulating genomic instability and tumor immune invasion.The expression of some rhythm genes was significantly correlated with the prognosis of cancer patients,and the expression level of some rhythm genes might be closely related to the efficacy of immune checkpoint blockade therapy.