Genomic Profiling of lower-grade gliomas subtype with distinct molecular and clinicopathologic characteristics via altered DNA-damage repair features

Abstract Background : Lower WHO grade II and III gliomas (LGGs) are characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA Damage Repair (DDR), its function in tumor biology, coupling with the transcriptome and tumor microenvironment (TM) and its possible impact for tumor development. Methods : In this study, we analyzed gene expression profiles downloaded from TCGA, CGGA, and GEO databases. The DNA damage repair (DDR) alterations among LGG have been studied via multi-omics data integration. For this, LGG patients have been grouped into distinct subtypes (DDR-activated and the DDR-suppressed subtype) based on different clinicalparameters and molecular characteristics. The differences in gene mutation, immune spectrum, and immune cell infiltration between the two DDR subtypes were compared. We generated DDR subtype features (DDR scores) to implement DDR classification in LGG and confirmed the results using a multi-layer data cohort. In addition, the characteristics of DDR subtypes predicted by immunotherapy responses and their roles in the tumor immune microenvironment (TIM) were explored. Result : The DDR activation subgroup was found to be associated with poorer overall survival based on molecular subtypes, and clinicopathological features of advanced-age and higher-grade were more common in the DDR-activated subgroup. DDR-suppressed subtypes also exhibited more frequent mutations in IDH1. We also found significant upregulation of activated immune cells in the DDR-activated subgroup, which indicates significant influence posed by infiltration of immune cells on tumor progression as well as immunotherapeutic responses. In addition, six DDR genes were selected to construct a DDR signature of LGG, dividing patients into low- and high-risk groups. Within the IMvigor210 cohort, there were fewer CR/PR groups in the high-score patients, as well as concomitant shorter survival times. CR/PR group had higher DDR characteristics scores compared to the SD/PD group. QRT-PCR results showed that the expression levels of CDK1 , CDK2 , TYMS , SMC4 , and WEE1 were found to be considerably higher for LGG samples compared to normal brain tissue samples (p < 0.05). Conclusion : In conclusion, our work sheds light on the DDR heterogeneity of LGG and advances our knowledge of the molecular pathways in DDR that lead to LGG.