Abstract 1412: Comprehensive characterization of clock genes in human cancers

Abstract

Abstract Cancer chronotherapy has been considered to optimize the balance of anti-tumor effects and toxicity. To develop cancer chronotherapy, the first crucial step is to understand the significant roles of clock genes in cancer. Circadian machinery is controlled by two main transcription auto-regulatory feedback loops, which including 14 core circadian genes. Core clock genes have at least one paralog gene may be functionally redundant in circadian regulation. Dysregulation of circadian genes promotes tumorigenesis through mechanisms that include the cell cycle, DNA damage and metabolism. However, there has been no comprehensive analysis to characterize the roles of circadian genes and circadian rhythms in tumorigenesis and to assess their potential utility in cancer chronotherapy. We determined genetic and epigenetic alterations of clock genes in human cancer, and explore clock gene clinical effect through integrative analysis, based on The Cancer Genome Atlas (TCGA) profiles contained DNA, RNA, protein, epigenetic levels and clinical data. Our results suggested several clock genes may function as oncogene, such as ARNTL2, NR1D1, and NPAS2, while several other clock genes may function as tumor suppressors, such as PERs, CRYs, RORs. We revealed disruption and reprogramming of circadian rhythms across patient samples by showing significantly reduced number of genes correlated to clock genes. We further showed that transcriptional dysregulation of clock genes is strongly associated with patient survival, tumor stage and subtype. Taken together, our results provide the comprehensive analysis of clock system across different cancer types and expected outcomes will lay the groundwork for the future development of cancer chronotherapy. Citation Format: Youqiong Ye, Yu Xiang, Joseph Takahashi, Gordon Mills, Seung-Hee Yoo, Leng Han. Comprehensive characterization of clock genes in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1412.