A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy

Our plain-English summary of A comprehensive pancancer analysis reveals the potential value of RAR-related orphan receptor C (RORC) for cancer immunotherapy, by S. He, J. Yu, W. Sun, et al (Frontiers in Genetics, 2022).

The study

• Authors: S. He, J. Yu, W. Sun, Y. Sun, M. Tang, B. Meng, Y. Liu, J. Li
• Journal: Frontiers in Genetics
• Published: 2022;13:969476
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: RAR-related orphan receptor C (RORC) plays an important role in autoimmune responses and inflammation. However, its function in cancer immunity is still unclear. Its potential value in cancer immunotherapy (CIT) needs to be further studied. Methods: Expression and clinical data for 33 cancers were obtained from UCSC-Xena. The correlation between RORC expression and clinical parameters was analyzed using the limma software package to assess the prognostic value of RORC. Timer2.0 and DriverDBv3 were used to analyze the RORC mutation and methylation profiles. RORC-associated signaling pathways were identified by GSEA. The correlations of RORC expression with tumor microenvironment factors were further assessed, including immune cell infiltration (obtained by CIBERSORT) and immunomodulators (in pancancer datasets from the Tumor-Immune System Interactions and Drug Bank [TISIDB] database). In addition, the correlations of RORC with four CIT biomarkers (tumor mutational burden, microsatellite instability, programmed death ligand-1, and mismatch repair) were explored. Furthermore, three CIT cohorts (GSE67501, GSE168204, and IMvigor210) from the Gene Expression Omnibus database and a previously published study were used to determine the association between RORC expression and CIT response. Results: RORC was differentially expressed in many tumor tissues relative to normal tissues (20/33). In a small number of cancers, RORC expression was correlated with age (7/33), sex (4/33), and tumor stage (9/33). Furthermore, RORC expression showed prognostic value in many cancers, especially in kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and mesothelioma (MESO). The mutation rate of RORC in most cancer types was low, while RORC was hypermethylated or hypomethylated in multiple cancers. RORC was associated with a variety of biological processes and signal transduction pathways in various cancers. Furthermore, RORC was strongly correlated with immune cell infiltration, immunomodulators, and CIT biomarkers. However, no significant association was found between RORC and CIT response in the three CIT cohorts. Conclusion Our findings revealed the potential immunotherapeutic value of RORC for various cancers and provides preliminary evidence for the application of RORC in CIT.

Copyright © 2022 He, Yu, Sun, Sun, Tang, Meng, Liu and Li.

In plain English

This was a computer-based analysis of publicly available gene data, not a study of asbestos exposure. The authors examined a gene called RORC, which is involved in immune responses, in tumor samples from 33 cancer types in The Cancer Genome Atlas database. These included 86 mesothelioma tumor samples. The authors also looked at three groups of patients given immunotherapy drugs for bladder cancer, kidney cancer or metastatic melanoma. In mesothelioma, higher RORC expression was reported as a protective factor for overall, disease-specific and progression-free survival; the text gives no hazard ratios. In mesothelioma, RORC was positively correlated with mast cell infiltration. Among the 45 immune-stimulating genes examined across all cancers, RORC's strongest negative correlation was with a gene called NT5E, in mesothelioma. In all three immunotherapy groups, RORC expression did not differ significantly between patients who responded and those who did not. The authors concluded that their findings provide preliminary evidence for using RORC in cancer immunotherapy. They noted that the data were retrospective and that animal experiments and prospective studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective bioinformatics analysis of public gene-expression and clinical databases (pan-cancer analysis)
• Who was studied: Tumor samples from 33 cancer types in TCGA, including 86 mesothelioma tumor samples with no adjacent normal tissue; normal tissues from GTEx; plus three immunotherapy cohorts: IMvigor210 (bladder cancer treated with atezolizumab, described in the article as 34 patients), GSE67501 (renal cell carcinoma treated with a PD-1 inhibitor) and GSE168204 (metastatic melanoma treated with a PD-1 inhibitor)
• Exposure: No asbestos or fiber exposure was studied; the factor examined was expression of the RORC gene in tumor tissue
• Main results:
  • In Cox regression, RORC expression was a protective factor for overall survival in mesothelioma (and in KIRC, LIHC, SKCM and THYM) but a risk factor in LGG
  • RORC expression was a protective factor for disease-specific survival in mesothelioma, BLCA, KIRC and LUAD
  • RORC expression was a protective factor for progression-free survival in mesothelioma and several other cancers
  • In Kaplan-Meier analyses, RORC was significantly associated with overall survival in mesothelioma, among other cancers
  • In mesothelioma, RORC expression was positively correlated with mast cell infiltration
  • Among the 45 immunostimulators analyzed across cancers, RORC's strongest negative correlation was with NT5E in mesothelioma
  • In mesothelioma, RORC was associated with Toll-like receptor and RIG-I-like receptor signaling pathways (GSEA)
  • The RORC mutation rate was highest in skin cutaneous melanoma (26/468); the mutation rate was low in most cancers
  • In all three immunotherapy cohorts, RORC expression did not differ significantly between responders and non-responders, with a non-significant trend toward better response with low RORC expression
• The authors' conclusion: The authors concluded that their findings provide preliminary evidence for the application of RORC in cancer immunotherapy
• Limitations the authors state:
  • Only three immunotherapy cohorts were examined, which made it difficult to fully clarify how RORC relates to immunotherapy response
  • Expression and prognosis data were obtained retrospectively from public databases
  • Validation in animal experiments and prospective multicenter, large-sample studies is needed

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Inflammation, Tumor Microenvironment, Biomarker, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI-H), Carcinoma, Mesothelioma.

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