Prognostic role of PHYH for overall survival (OS) in clear cell renal cell carcinoma (ccRCC)

Abstract

This study attempts to evaluate the prognostic role of PHYH for overall survival (OS) in clear cell renal cell carcinoma (ccRCC) by means of publicly available data from The Cancer Genome Atlas (TCGA). Clinical pathologic features and PHYH expression were downloaded from the TCGA database and relationships between them were analyzed by univariate and multivariate Cox regression analyses. Gene Set Enrichment Analysis (GSEA) and gene-gene interactions were also performed between tissues with different PHYH expression levels. PHYH expression levels were significantly lower in patient with ccRCC compared with normal tissues (p = 1.156e-19). Kaplan-Meier survival analysis showed that high expression of PHYH had a better prognosis than low expression (p = 9e-05). Moreover, PHYH expression was also significantly associated with high grade (G2-4, p = 0.025), high stage (StageIII & IV, p = 5.604e-05), and high level of stage_T (T3-4, p = 4.373e-05). Univariate and multivariate Cox regression analyses indicated that PHYH could be acted as an independent prognostic factor (p < 0.05). Nomogram including clinical pathologic features and PHYH expression were also provided. GSEA revealed that butanoate metabolism, histidine metabolism, propanoate metabolism, pyruvate metabolism, tryptophan metabolism, PPAR signalling pathway, and renin-angiotensin system were differentially enriched in PHYH high-expression phenotype. ICGC database was utilized to verify the expression level and survival benefit of PHYH (both p < 0.05). We suspect that elevated PHYH expression may be served as a potential prognostic molecular marker of better survival in ccRCC. Besides, alpha-oxidation was closely regulated by PHYH, and PPAR signalling, pyruvate metabolism, butanoate metabolism, and RAS might be the key pathways regulated by PHYH in CCRC.

Keywords: Clear cell renal cell carcinoma; PHYH; Prognosis; TCGA.

Fig. 1

a Boxplot showed that the PHYH expression in ccRCC tissues (n = 538) was different from that in para-cancerous tissues (n = 72) in TCGA dataset; b pairwise boxplot showed that the PHYH expression in ccRCC tissues (n = 72) was also different from that in matched para-cancerous tissues (n = 72) in TCGA dataset; c Impact of PHYH expression on overall survival in ccRCC patients in TCGA cohort. d ROC curve analysis of significantly PHYH expression between normal patients and ccRCC patients with tumor

Fig. 2

Association with PHYH expression and clinicopathologic characteristics, including a grade, b stage, and c primary tumor size (T)

Fig. 3

a Univariate Cox regression analysis of PHYH expression and clinicopathologic characteristics; b multivariate Cox regression analysis of PHYH expression and clinicopathologic characteristics; c ROC curves analysis of PHYH expression and clinicopathologic characteristics. d Nomogram of PHYH expression and clinicopathologic characteristics

Fig. 4

a PPI network of PHYH in ccRCC cases. b Relationships between PHYH and microsatellite instability (MSI). c Associations between PHYH and immune checkpoint inhibitors. d Relationships between PHYH and the methods of immunity

Fig. 5

Enrichment plots from gene set enrichment analysis (GSEA). GSEA results showing a butanoate metabolism, b histidine metabolism, c propanoate metabolism, d pyruvate metabolism, e tryptophan metabolism, f PPAR signalling pathway, and g renin–angiotensin system are differentially enriched in PHYH-related ccRCC. h Comparison of enrichment plots for all significant pathways

Fig. 6

Verification of PHYH in ccRCC: a the expression level of PHYH in various cancers by GTEx and TCHA; b the boxplot of PHYH in ICGC database; c the survival analysis of PHYH in ICGC database; d the HPA database indicated the difference of immunohistochemistry in normal and kidney cancers