Abstract
Classical Non-homologous End Joining (NHEJ) pathway is the mainstay of cellular response to DNA double strand breaks. While aberrant expression of genes involved in this pathway has been linked with genomic instability and drug resistance in several cancers, limited information is available about its clinical significance in colon cancer. We performed a comprehensive analysis of seven essential genes, including XRCC5, XRCC6, PRKDC, LIG4, XRCC4, NHEJ1, and PAXX of this pathway, in colon cancer using multi-omics datasets, and studied their associations with molecular and clinicopathological features, including age, gender, stage, KRAS mutation, BRAF mutation, microsatellite instability status and promoter DNA methylation in TCGA colon cancer dataset. This analysis revealed upregulation of XRCC5, PRKDC, and PAXX in colon cancer compared to normal colon tissues, while LIG4 and NHEJ1 (XLF) displayed downregulation. The expression of these genes was independent of age and KRAS status, while XRCC5, PRKDC, and LIG4 exhibited reduced expression in BRAF mutant tumors. Interestingly, we observed a strong association between XRCC6, XRCC5, PRKDC and LIG4 overexpression and microsatellite instability status of the tumors. In multivariate analysis, high PAXX expression emerged as an independent prognostic marker for poor overall and disease specific survival. We also observed hypomethylation of PAXX promoter in tumors, which exhibited a strong correlation with its overexpression. Furthermore, PAXX overexpression was also associated with several oncogenic pathways as well as a reduction in numbers of tumor-infiltrating lymphocytes.
Highlights
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the third most common cause of cancer related deaths worldwide (Bray et al, 2018; Rawla et al, 2019)
To determine the expression pattern of core Non-homologous End Joining (NHEJ) genes in colon cancer, we performed Oncomine analysis for XRCC6 (Ku70), XRCC5 (Ku80), PRKDC (DNA-PKcs), XRCC4 (XRCC4), LIG4 (DNA ligase 4), NHEJ1 (XLF), and PAXX (PAXX/XLS). It provided the advantage of analyzing several datasets in parallel to assess the general expression pattern of these genes. This analysis revealed significant upregulation of five genes, (XRCC6, XRCC4, PRKDC, XRCC4, and PAXX) and downregulation of two (LIG4 and NHEJ1) NHEJ pathway genes, in tumor tissues compared to the normal tissues (Table 1)
Consistent with the Oncomine analysis, comparison of all available normal (n = 41) and tumor tissues (n = 469) revealed overexpression of XRCC6, XRCC5, PRKDC, XRCC4, and PAXX in tumors compared to normal tissues, while LIG4 and NHEJ1 displayed lower expression in the tumor tissues (Figure 1A)
Summary
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the third most common cause of cancer related deaths worldwide (Bray et al, 2018; Rawla et al, 2019). It represents a group of heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations (The Cancer Genome Atlas Network, 2012). HRR functions by using a homologous DNA strand as a template to perform error free repair at DSB sites. Alt-EJ is a less characterized mechanism which works as a backup for both HRR and NHEJ in case of excessive DNA damage, and utilizes micro-homologies between distant DNA sites for template dependent repair
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