AUTHOR=Arora Mohit , Kumari Sarita , Singh Jay , Chopra Anita , Chauhan Shyam S. 

TITLE=PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2020.584053

DOI=10.3389/fmolb.2020.584053

ISSN=2296-889X

ABSTRACT=<p>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 <italic>XRCC5</italic>, <italic>XRCC6</italic>, <italic>PRKDC</italic>, <italic>LIG4</italic>, <italic>XRCC4</italic>, <italic>NHEJ1</italic>, and <italic>PAXX</italic> of this pathway, in colon cancer using multi-omics datasets, and studied their associations with molecular and clinicopathological features, including age, gender, stage, <italic>KRAS</italic> mutation, <italic>BRAF</italic> mutation, microsatellite instability status and promoter DNA methylation in TCGA colon cancer dataset. This analysis revealed upregulation of <italic>XRCC5</italic>, <italic>PRKDC</italic>, and <italic>PAXX</italic> in colon cancer compared to normal colon tissues, while <italic>LIG4</italic> and <italic>NHEJ1</italic> (XLF) displayed downregulation. The expression of these genes was independent of age and <italic>KRAS</italic> status, while <italic>XRCC5</italic>, <italic>PRKDC</italic>, and <italic>LIG4</italic> exhibited reduced expression in <italic>BRAF</italic> mutant tumors. Interestingly, we observed a strong association between <italic>XRCC6</italic>, <italic>XRCC5</italic>, <italic>PRKDC</italic> and <italic>LIG4</italic> overexpression and microsatellite instability status of the tumors. In multivariate analysis, high <italic>PAXX</italic> expression emerged as an independent prognostic marker for poor overall and disease specific survival. We also observed hypomethylation of <italic>PAXX</italic> promoter in tumors, which exhibited a strong correlation with its overexpression. Furthermore, <italic>PAXX</italic> overexpression was also associated with several oncogenic pathways as well as a reduction in numbers of tumor-infiltrating lymphocytes.</p>