ARNTL2

Abstract: Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., CLOCK, PER1, PER2, PER3, CRY2, NPAS2 and RORC) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted P < 0.05). Stratification according to molecular subtype revealed prognostic relevance for PER1, PER3, CRY2 and NFIL3 in the ER+/HER2- subgroup, CLOCK and NPAS2 in the ER-/HER2- subtype, and ARNTL2 in HER2+ breast cancer. In the multivariate Cox model, only PER3 (HR = 0.66; P = 0.016) and RORC (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.

Abstract: Aims: Circadian clock genes are involved in the development of drug-induced behaviors and regulate neurotransmission pathways in addiction. Our aim was to study whether circadian clock gene polymorphisms predispose to alcohol dependence or abuse or other alcohol-related characteristics. Methods: The study sample comprised of 512 individuals having alcohol dependence or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)) and their 511 age- and sex-matched controls. This population-based sample was drawn from a cohort ( n = 7415), representative of the Finnish general population aged 30 and over. Altogether 42 single-nucleotide polymorphisms of 19 genes related to the circadian pacemaker system were genotyped. Results: ARNTL rs6486120 T + allelic status ( P = 0.0007, q = 0.17), ADCYAP1 rs2856966 GG genotype ( P = 0.0006, q = 0.17) and VIP CC haplotype (rs3823082–rs688136) ( P = 0.0006) were suggestively associated with alcohol consumption in socially drinking controls. ARNTL2 GT haplotype (rs7958822–rs4964057) associated suggestively with alcohol abuse diagnosis ( P = 0.0013). Earlier findings on the associations of DRD2 and NPY with alcohol dependence were supported: DRD2/ANKK1 Taq1A1 increased ( P = 0.04) and NPY Pro7 decreased ( P = 0.01) the risk of alcohol dependence. Conclusions: ARNTL , ARNTL2 , VIP and ADCYAP1 were indicated as having influence on alcohol use or abuse. The role of DRD2 and NPY on alcohol dependence was also supported.

Abstract: Aims: Circadian clock genes are involved in the development of drug-induced behaviors and regulate neurotransmission pathways in addiction. Our aim was to study whether circadian clock gene polymorphisms predispose to alcohol dependence or abuse or other alcohol-related characteristics. Methods: The study sample comprised of 512 individuals having alcohol dependence or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)) and their 511 age- and sex-matched controls. This population-based sample was drawn from a cohort ( n = 7415), representative of the Finnish general population aged 30 and over. Altogether 42 single-nucleotide polymorphisms of 19 genes related to the circadian pacemaker system were genotyped. Results: ARNTL rs6486120 T + allelic status ( P = 0.0007, q = 0.17), ADCYAP1 rs2856966 GG genotype ( P = 0.0006, q = 0.17) and VIP CC haplotype (rs3823082–rs688136) ( P = 0.0006) were suggestively associated with alcohol consumption in socially drinking controls. ARNTL2 GT haplotype (rs7958822–rs4964057) associated suggestively with alcohol abuse diagnosis ( P = 0.0013). Earlier findings on the associations of DRD2 and NPY with alcohol dependence were supported: DRD2/ANKK1 Taq1A1 increased ( P = 0.04) and NPY Pro7 decreased ( P = 0.01) the risk of alcohol dependence. Conclusions: ARNTL , ARNTL2 , VIP and ADCYAP1 were indicated as having influence on alcohol use or abuse. The role of DRD2 and NPY on alcohol dependence was also supported.

Abstract: Although dysfunctional circadian clock has emerged as a hallmark of cancer, fundamental gaps remain in our understanding of the underlying mechanisms involved. Here, we systematically analyze the core genes of the circadian clock (CLOCK, ARNTL, ARNTL2, NPAS2, NR1D1, NR1D2, CRY1, CRY2, RORA, RORB, RORC, PER1, PER2, and PER3) across a broad range of cancers. To our surprise, core negative regulators (PER1, PER2, PER3, CRY1, and CRY2) are consistently downregulated, while core positive regulators show minimal alterations, indicating disrupted circadian clock in cancers. Such downregulation originates from copy number variations where heterozygous deletion predominates. The disrupted circadian clock is significantly associated with patient outcome. Further pathway enrichment analysis suggests that the circadian clock widely impacts 45 pathways such as the Ras signaling pathway and T cell receptor signaling pathway. By using state-of-the-art immune cell deconvolution and pathway quantification, we demonstrate that abnormal circadian clock contributes to T cell exhaustion and global upregulation of immune inhibitory molecules such as PD-L1 and CTLA-4. In summary, the rhythm of the circadian clock is disrupted in cancers. Abnormal circadian clock linked with immune evasion may serve as a potential hallmark of cancer.