PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer.
PAXX, Not NHEJ1 Is an Independent Prognosticator in Colon Cancer.
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DOI：
10.3389/fmolb.2020.584053
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发表时间：
2020
影响因子：
5
通讯作者：
Chauhan SS
中科院分区：
文献类型：
--
作者：
Arora M;Kumari S;Singh J;Chopra A;Chauhan SS
经典的非同源末端连接（NHEJ）途径是细胞对DNA双链断裂反应的主要途径。虽然参与该途径的基因的异常表达与几种癌症中的基因组不稳定性和耐药性有关，但关于其在结肠癌中的临床意义的信息有限。我们利用多组学数据集对该通路的7个必需基因（包括XRCC5、XRCC6、PRKDC、LIG4、XRCC4、NHEJ1和PAXX）进行了全面分析，并研究了它们与TCGA结肠癌数据集中的分子和临床病理特征（包括年龄、性别、分期、KRAS突变、BRAF突变、微卫星不稳定性状态和启动子DNA甲基化）的相关性。该分析揭示了与正常结肠组织相比，结肠癌中XRCC5、PRKDC和PAXX的上调，而LIG4和NHEJ1（XLF）显示下调。这些基因的表达与年龄和KRAS状态无关，而XRCC5、PRKDC和LIG4在BRAF突变型肿瘤中的表达降低。有趣的是，我们观察到XRCC6、XRCC5、PRKDC和LIG4过表达与肿瘤的微卫星不稳定状态之间存在强相关性。在多变量分析中，PAXX高表达是总体和疾病特异性生存率差的独立预后标志。我们还观察到肿瘤中PAXX启动子的低甲基化，这与其过表达有很强的相关性。此外，PAXX过表达还与几种致癌途径以及肿瘤浸润淋巴细胞数量的减少有关。
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.