Renal Carcinoma Is Associated With Increased Risk of Coronavirus Infections

Abstract

Background: The current COVID-19 pandemic has affected most severely people with old age, or with comorbidities like hypertension, diabetes mellitus, and cancer. Cancer patients are twice more likely to contract the disease because of the malignancy or treatment-related immunosuppression; hence identification of the vulnerable population among these patients is essential.Method: We took a bioinformatics approach to analyze the gene and protein expression data of these coronavirus receptors (DPP4, ANPEP, ENPEP, TMPRSS2) in human normal and cancer tissues of multiple organs including the brain, liver, kidney, heart, lung, skin, GI tract, pancreas, endocrine tissues, and the reproductive organs. RNA-Seq data from The Cancer Genome Atlas (TCGA) and GTeX databases were used for extensive profiling analysis of these receptors across 9,736 tumors and 8,587 normal tissues comparing coronavirus receptors. Protein expression from immunohistochemistry data was assessed from The Human Protein Atlas database including 144 samples, corresponding to 48 different normal human tissue types, and 432 tumor samples from 216 different cancer patients. The correlations between immune cell infiltration, chemokine, and cytokines were investigated via Tumor Immune Estimation Resource (TIMER) and TCGA.Result: We found that among all, renal tumor and normal tissues exhibited increased levels of ACE2, DPP4, ANPEP, and ENPEP. Our results revealed that TMPRSS2 may not be the co-receptor for coronavirus infection in renal carcinoma patients. The other receptors DPP4, ANPEP, and ENPEP may act as the compensatory receptor proteins to help ACE2. The receptors' expression levels were variable in different tumor stage, molecular, and immune subtypes of renal carcinoma. Intriguingly, in clear cell renal cell carcinomas, coronavirus receptors were associated with high immune infiltration, markers of immunosuppression, and T cell exhaustion.Conclusion: Our study indicates that CoV receptors may play an important role in modulating the immune infiltrate and hence cellular immunity in renal carcinoma. As our current knowledge of pathogenic mechanisms will improve, it may help us in designing focused therapeutic approaches.

Angiotensin-Converting Enzyme 2 Protein Is Overexpressed in a Wide Range of Human Tumour Types: A Systematic Tissue Microarray Study on >15,000 Tumours

“…Our analysis of 12,664 tumours of 119 different subtypes identified renal cell carcinomas derived from the proximal tubulus and colorectal adenocarcinomas as the most frequently ACE2-positive cancer types, followed by gastric adenocarcinoma, ductal and papilla Vaterii-derived pancreatic adenocarcinoma as well as cholangiocellular and hepatocellular carcinoma of the liver. This finding is in complete agreement with data from “The Cancer Genome Atlas” (TCGA) summarised in two recent publications [ 7 , 10 ]. Other tumour entities which were often ACE2-positive were too rare for being separately analysed within ICGC/TCGA studies, for example clear cell carcinomas of the ovary and the endometrium which resemble the commonly positive clear cell carcinomas of the kidney and mucinous carcinomas of the ovary which resemble the commonly positive colorectal adenocarcinomas.…”

“…Previous analyses of normal tissues have identified ACE2 protein expression in at least one cell type of the kidney, testis, placenta, stomach, duodenum, small intestine, colon, rectum, gallbladder, liver, pancreas, thyroid gland, heart muscle, few cells in the respiratory epithelium, and endothelial cells of small vessels [ 5 ]. RNA-based analyses have also demonstrated that ACE2 expression occurs to a varying extent in miscellaneous cancer types [ 7 , 8 , 9 , 10 ], and upregulation of ACE2 has been linked to adverse cancer features in renal clear cell carcinoma, breast cancer, thyroid cancers and gallbladder carcinoma [ 11 , 12 , 13 , 14 ]. It has also been speculated that—in addition to a stressed immune system and poor general health status of cancer patients—presence of a large number of ACE2-expressing cancer cells might facilitate virus replication and contribute to the high COVID-19 mortality of cancer patients [ 15 , 16 , 17 ].…”

Emerging Role of Neuropilin-1 and Angiotensin-Converting Enzyme-2 in Renal Carcinoma-Associated COVID-19 Pathogenesis

“…In addition, ACE2 expression in KIRC and KIRP was significantly upregulated compared to healthy conditions ( Figure 2 CD). The findings of our investigation were further supported by Tripathi et al, who analyzed the RNA-Seq data of various organs from the TCGA and GTsX databases, revealing that patients with renal carcinoma are expected to be at higher risk of SARS-CoV-2 infection [ 27 ]. Another study also revealed that renal carcinomas are reported to be associated with an increased risk of coronavirus infection due to the immune-modulating role of ACE2 in renal cancers [ 27 ].…”

“…The findings of our investigation were further supported by Tripathi et al, who analyzed the RNA-Seq data of various organs from the TCGA and GTsX databases, revealing that patients with renal carcinoma are expected to be at higher risk of SARS-CoV-2 infection [ 27 ]. Another study also revealed that renal carcinomas are reported to be associated with an increased risk of coronavirus infection due to the immune-modulating role of ACE2 in renal cancers [ 27 ]. Therefore, these results suggest that, along with the ACE2 expression, NRP1 expression might be involved in renal failure due to SARS-CoV-2 in renal cancer patients.…”

Impact of SARS-CoV-2 Pandemic on Kidney Cancer Management

“…The survival curves demonstrated that in clear cell RCC (as well as in the case of uveal melanoma and prostate adenocarcinoma) high ACE2 expression was related to a good prognosis. ACE inhibitors, widely used as therapeutic agents for hypertension treatment, are reported to upregulate ACE2 receptor expression [124]. Therefore, it was assumed that the use of ACE inhibitors, by increasing ACE2 expression levels, may improve survival rates in RCC patients.…”