Pan-cancer analyses of clinical prognosis, immune infiltration, and immunotherapy efficacy for TRPV family using multi-omics data.

Background: Transient receptor potential cation channel subfamily V (TRPV) play an essential in cancer initiation, progression, and treatment. TRPV expression alteration are shown relate to multiple cancers prognosis and treatment of cancers but are less-studied in pan-cancer. In this study, we characterize the clinical prediction value of TRPV at pan-cancer level.

Methods: Several databases were used to examine the transcript expression difference in tumor vs. normal tissue, copy-number variant (CNV) and single nucleotide polymorphisms (SNP) mutation of each TRPV members in pan-cancer, including The Cancer Genome Atlas (TCGA) and cBioPortal. We performed K-M survival curve and univariate Cox regression analyses to identify survival and prognosis value of TRPV. CellMiner were selected to explore drug sensitivity. We also analyzed association between tumor mutation burden (TMB), microsatellite instability (MSI), tumor immune microenvironment and TRPV family genes expression. Moreover, we investigated the relationship between TRPVs expression and effectiveness of immunotherapy in multiple cohorts, including one melanoma (GSE78220), one renal cell carcinoma (GSE67501), and three bladder cancer cohorts (GSE111636, IMvigor210, GSE176307 and our own sequencing dataset (TRUCE-01)), and further analyzed the changes of TRPVs expression before and after treatment (tislelizumab combined with nab-paclitaxel) of bladder cancer. Next, we made a special effort to investigate and study biological functions of TRPV in bladder cancer using gene set enrichment analysis (GSEA), and conducted immune infiltration analysis with TRPVs family genes expression, copy number or somatic mutations of bladder cancer by TIMER 2.0. Finally, real-time PCR and protein expression validation of TRPVs within 10 paired cancer and para-carcinoma tissue samples, were also performed in bladder cancer.

Results: Only TRPV2 expression was lower in most cancer types among TRPV family genes. All TRPVs were correlated with survival changes. Amplification was the significant gene alternation in all TRPVs. Next, analysis between TRPVs and clinical traits showed that TRPVs were related to pathologic stage, TNM stage and first course treatment outcome. Moreover, TRPV expression was highly correlated with MSI and TMB. Immunotherapy is a research hotspot at present, our result showed the significant association between TRPVs expression and immune infiltration indicated that TRPV expression alternation could be used to guide prognosis. In addition, we also discovered that the expression level of TRPV1/2/3/4/6 was positively or negatively correlated with objective responses to anti-PD-1/PD-L1 across multiple immunotherapy cohort. Further analysis of drug sensitivity showed the value to treatment. Based on the above analysis, we next focused on TRPV family in bladder cancer. The result demonstrated TRPV also played an important role in bladder cancer. Finally, qPCR assay verified our analysis in bladder cancer.

Conclusion: Our study firstly revealed expression and genome alternation of TRPV in pan-cancer. TRPV could be used to predict prognosis or instructing treatment of human cancers, especially bladder cancer.