Prognostic and immunological significance of calcium-related gene signatures in renal clear cell carcinoma

An Liu; Fei Li; Bao Wang; Le Yang; Hai Xing; Chang Su; Li Gao; Minggao Zhao; Lanxin Luo

doi:10.3389/fphar.2022.1055841

Prognostic and immunological significance of calcium-related gene signatures in renal clear cell carcinoma

Front Pharmacol. 2022 Dec 14:13:1055841. doi: 10.3389/fphar.2022.1055841. eCollection 2022.

Authors

An Liu¹, Fei Li^{1

2}, Bao Wang³, Le Yang¹, Hai Xing⁴, Chang Su^{1

5}, Li Gao³, Minggao Zhao^{1

6}, Lanxin Luo^{1

6}

Affiliations

¹ Precision Pharmacy and Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
² Department of Pharmacy, The Hospital of 92880 Troops, PLA Navy, Zhoushan, Zhejiang, China.
³ Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
⁴ Medical Affairs Division, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
⁵ Shaanxi Provincial Corps, Chinese People's Armed Police Force, Xi'an, Shaanxi, China.
⁶ Institute of Medical Research, Northwestern Polytechnical University, Xi'an, Shaanxi, China.

Abstract

Background: Calcium signaling is implicated in multiple processes including immune response that important in tumor progression. Kidney renal clear cell carcinoma (KIRC) is the most frequent histological type of renal cell carcinoma with up to a third of cases develop metastases. As a result of a lack of in-depth understanding of the mechanisms underlying KIRC, treatment options have been limited. Here, we aim to comprehensively investigate the landscape of Ca²⁺ channels, pumps and exchangers in KIRC patients. Methods: The mRNA expression profiles and gene variations of 58 calcium-related genes (CRGs) in KIRC patients and normal control cases were downloaded from TCGA database. CRGs-related risk score was constructed to quantify calcium patterns by using least absolute shrinkage and selection operator (LASSO) regression. The prognostic value, biological functions, immune landscape and therapeutic sensitivities based on CRGs-related risk score were then evaluated using multiple methods. Finally, key gene of CRGs was identified by weighted gene co-expression network analysis (WGCNA). TCGA-CPTAC, GSE53757 datasets, as well as human tissues were used for validation. Results: KIRC patients had significant differences in CRG expression, prognosis, and biological functions between two CRG clusters. CRGs-related risk score was then determined. The prognosis, tumor mutation burden, immune cell infiltration, immune checkpoints, and the response of targeted inhibitors were remarkably different between high and low CRGs-related risk subtypes. CRGs-related high-risk subtype was characterized by immunosuppressive microenvironment with poor prognosis. Meanwhile, several targeted drugs showed distinct sensitivity between CRGs-related risk subtypes. Finally, TRPM3 was identified as a key CRG based on risk score in KIRC patients. TRPM3 mRNA and protein expression were significantly lower in KIRC tumors than in normal controls. Low TRPM3 expression was associated with poor prognosis in KIRC patients. Conclusion: Our study highlighted the promising prognostic value of CRGs in KIRC tumors. The evaluation of CRGs-related risk score will contribute to predicting prognosis and clinical therapy in KIRC patients.

Keywords: calcium; immune response; immunity; kidney renal clear cell carcinoma; prognosis.