PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma

Abstract

Lower-grade glioma (LGG) is a diffuse infiltrative tumor of the central nervous system, which lacks targeted therapy. We investigated the role of Podocan-like 1 (PODNL1) methylation in LGG clinical outcomes using the TCGA-LGG transcriptomics dataset. We identified four PODNL1 CpG sites, cg07425555, cg26969888, cg18547299, and cg24354933, which were associated with unfavorable overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analysis after adjusting for age, gender, tumor-grade, and IDH1-mutation. In multivariate analysis, the OS and DFS hazard ratios ranged from 0.44 to 0.58 (p < 0.001) and 0.62 to 0.72 (p < 0.001), respectively, for the four PODNL1 CpGs. Enrichment analysis of differential gene and protein expression and analysis of 24 infiltrating immune cell types showed significantly increased infiltration in LGGs and its histological subtypes with low-methylation levels of the PODNL1 CpGs. High PODNL1 expression and low-methylation subgroups of the PODNL1 CpG sites were associated with significantly increased PD-L1, PD-1, and CTLA4 expressions. PODNL1 methylation may thus be a potential indicator of immune checkpoint blockade response, and serve as a biomarker for determining prognosis and immune subtypes in LGG.

Small Leucine-Rich Proteoglycan PODNL1 Identified as a Potential Tumor Matrix-Mediated Biomarker for Prognosis and Immunotherapy in a Pan-Cancer Setting

“…PODNL1 is an important member of the SLRP family which includes ubiquitous ECM components involved in matrix organization and signaling regulation in TME [4]. At present, a number of studies have revealed the promoting role of PODNL1 in tumor proliferation and EMT [14][15][16][17][18]. In high-grade glioma cell lines, PODNL1 has been demonstrated to stimulate cell proliferation and migration via the regulation of the Akt-mTOR axis [16].…”

“…In particular, SLRPs have a class V member, named podocan-like 1 (PODNL1), which is found to be highly expressed in bone, glioma, bladder and ovarian cancers, representing a potential prognostic biomarker [14][15][16][17][18]. Its high expression together with the presence of low-methylation in its CpG sites is coupled with significantly increased expressions of PD-1, PD-L1, and CTLA4 in glioma [17]. Its overexpression in glioma cells is even believed to remarkably promote the mesenchymal-related biomarkers including vimentin, N-cadherin, snail, and fibronectin [16].…”

Autophagy related DNA methylation signature predict clinical prognosis and immune microenvironment in low-grade glioma

“…For example, Wang et al demonstrated that hypermethylation of the miR-338-5p promoter regulated the aberrant expression of ETS-1, which was a key regulator of tumor cell proliferation and invasion, and was associated with prognosis of astrocytoma patients (35). There was also a public database-based bioinformatics analysis showing that PODNL1 methylation acted as a prognostic biomarker and correlates with immune infiltration and immune checkpoints in LGG (36). da Costa Rosa et al evaluated the effect of a DNA demethylating agent combined with all-trans retinoic acid in IDH1 mutant gliomas, and the combination of 5-Aza and atRA reduced the growth of IDH1 R132H glioma cells and increased differentiation and apoptosis (37).…”

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“…No tecido muscular destacamos o aumento da expressão dos genes EDN1, MRC1, CDC6 e CCBE1 e a redução da expressão dos genes SPATA3, TNP2, FSCB, PRM2, IQCF1 e CDKN1A O gene PODNL1 (Podocan Like 1) pertence à família dos pequenos proteoglicanos ricos em leucina (SLRP). Ainda não tem função conhecida, mas pode estar associada a processos que envolvam a matriz extracelular (NOOR et al, 2021). Em humanos, é um marcador de prognóstico de câncer de ovário (TENG; ZHENG, 2017) e glioma (NOOR et al, 2021).…”

“…Ainda não tem função conhecida, mas pode estar associada a processos que envolvam a matriz extracelular (NOOR et al, 2021). Em humanos, é um marcador de prognóstico de câncer de ovário (TENG; ZHENG, 2017) e glioma (NOOR et al, 2021). É expresso em diversos tecidos, com maiores níveis em placenta e testículos (FAGERBERG et al, 2014).…”