The expression and methylation of PITX genes is associated with the prognosis of head and neck squamous cell carcinoma

Abstract

<b>Background:</b> The <i>PITX</i> gene family, comprising <i>PITX1</i>, <i>PITX2</i>, and <i>PITX3</i>, is critical in organogenesis and has been evolutionary conserved in animals. <i>PITX</i> genes are associated with the advanced progression and poor prognosis of multiple cancers. However, the relationship between the <i>PITX</i> genes and head and neck squamous cell carcinoma (HNSC) has not been reported. <b>Methods:</b> We used data from The Cancer Genome Atlas (TCGA) to analyze the association between <i>PITX</i> mRNA expression and clinicopathological parameters of patients with HNSC. The prognostic value of <i>PITX</i> genes was evaluated using the Kaplan-Meier plotter. Multivariate Cox analysis was used to screen out prognosis-associated genes to identify better prognostic indicators. The potential roles of <i>PITX1</i> and <i>PITX2</i> in HNSC prognosis were investigated using the protein-protein interaction (PPI) network, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The correlation between <i>PITX1</i> and <i>PITX2</i> expression or methylation and immune cell infiltration was evaluated using the tumor-immune system interaction database (TISIDB). MethSurv was used to identify DNA methylation and its effect on HNSC prognosis. <b>Results:</b> <i>PITX</i> genes expression was correlated with different cancers. <i>PITX1</i> and <i>PITX2</i> expression was lower in the patients with HNSC. In HNSC, <i>PITX1</i> expression was significantly related to the clinical stage, histologic grade, and N stage, while <i>PITX2</i> expression was only significantly related to the histologic grade. The high expression of <i>PITX3</i> was significantly related to the histologic grade, T stage, and N stage. Survival analysis revealed that <i>PITX</i> genes had prognostic value in HNSC, which was supported by multivariate Cox analysis. PPI network and enrichment analysis showed that the genes interacting with <i>PITX1</i> and <i>PITX2</i> belonged predominantly to signaling pathways associated with DNA binding and transcription. Of the CpG DNA methylation sites in <i>PITX1</i> and <i>PITX2</i>, 28 and 22 were related to the prognosis of HNSC, respectively. Additionally, <i>PITX1</i> and <i>PITX2</i> expression and methylation was associated with tumor-infiltrating lymphocytes (TILs). <b>Conclusion:</b> The <i>PITX</i> genes were differentially expressed in patients with HNSC, highlighting their essential role in DNA methylation and tumor-infiltrating immune cell regulation, as well as overall prognostic value in HNSC.