Role of Circadian Rhythm-Related Genes in the Pathogenesis of Breast Cancer

Introduction: Circadian rhythm plays a crucial role in many physiological processes, such as genomic stability, DNA repair mechanisms, and apoptosis, and is often disrupted in breast cancer (BRCA). Therefore, this study aimed to elucidate the relationship between BRCA pathogenesis and circadian rhythm by comprehensively determining gene mutations, expression, and methylation profiles of circadian rhythms using bioinformatics tools.
Material and Methods: The genome and expression profiles of the BRCA cohort (n: 1085) were obtained using bioinformatics tools providing data from The Cancer Genome Atlas. PolyPhen-2, SIFT, and Mutation Assessor tools were used to estimate the oncogenic–pathogenic effects of the detected mutations in BRCA pathogenesis. STRING analysis was performed to better understand the functional relationships of mutant proteins in cellular processes. In addition to genome profiling, gene expression and methylation profiles were generated.
Results: In total, 64 mutations were identified in 9 genes. Of these 64 mutations, 20 were classified as pathogenic or oncogenic. CRY1 and PER1 gene expression was downregulated in patients with BRCA whereas TIMELESS was upregulated compared with the healthy group (p<0.01). The effect of m-RNA expression, which is considered a prognostic marker, on overall survival was found to be significant for decreased CLOCK (p=0.026) and CRY1 (p=0.025) levels. STRING analysis revealed that hub proteins interact with the acetyltransferases P300 and NONO, which are involved in sister chromatid cohesion.
Discussion and Conclusion: The results indicate that CRY2 and PER1 gene expression is downregulated in BRCA and that circadian rhythm disruption may be associated with BRCA development.

Keywords: Breast cancer; Circadian rhythm; Cryptochrome; Gene expression; Mutation