Comprehensive analysis of the causal risk factor from hypertension associated with prognosis and therapeutic response in renal cell carcinoma by multi-omics analysis and validation

Hypertension is one of the known renal cell carcinoma (RCC)-associated factors. However, the gene expression patterns in hypertension tissues and the mechanisms of hypertension and RCC comorbidity have not been fully analyzed. This study aims to use single-cell RNA sequencing (scRNA-seq) integrated with multi-omics to explore RCC-associated hypertension gene modules and the causative relationship between key genes and the risk of RCC. Heterogenic expression programs in cross-species scRNA-seq tissues were classified by non-negative matrix factorization (NNMF) using scRNA-seq data from aortic tissues of hypertensive patients and spontaneously hypertensive rats (SHR). Molecular subtyping was performed using the bulk-seq and whole exome sequencing (WES) data of pan-cancer and RCC from TCGA. The Lasso-cox machine model was used to explore the predictors of survival and drug response in both TCGA, ICGC, E-MTAB-1980 and IMmotion 151 cohort. A total of 19 tissues were applied to perform scRNA-seq and then test the key gene expression. Finally, summary-data-based Mendelian Randomization (SMR) was used to verify the expression level of genes and traits of hypertension and RCC based on summary-level data from GWAS and expression quantitative trait loci (eQTL) studies. Two independent cohorts of European with GWAS summary statistics were used: hypertension cohort (119,731 cases and 343,202 controls) and RCC cohort (600 cases and 455,676 controls). scRNA-seq analysis revealed that the cross-species HTN-gene module consisted of 48 genes, which could classify the 523 patients into two subgroups with different survival and responses to targeted therapies. The results were then validated in three independent ccRCC cohorts. The core gene-panel scores were significantly different in vascular endothelial cells (P < 0.01), which also distinguished the cells from resistant and hypertensive tumor cells (both P < 0.001). SMR analysis demonstrated that TNXB was a reliable causative factor of hypertension and the RCC risk factor in hypertension (pSMR = 0.0029) and RCC (pSMR = 0.0031). The results of the present study demonstrated that the HTN key genes were involved in the development of RCC and may represent potential therapeutic targets for the management of this complex disease.