Abstract
Transmembrane Channel-like (TMC) genes are critical in the carcinogenesis, proliferation, and cell cycle of human cancers. However, the multi-omics features of TMCs and their role in the prognosis and immunotherapeutic response of human cancer have not been explored. We discovered that TMCs 4-8 were commonly deregulated and correlated with patient survival in a variety of cancers. For example, TMC5 and TMC8 were correlated with the relapse and overall survival rates of breast cancer and skin melanoma, respectively. These results were validated by multiple independent cohorts. TMCs were regulated by DNA methylation and somatic alterations, such as TMC5 amplification in breast cancer (523/1062, 49.2%). Six algorithms concordantly uncovered the critical role of TMCs in the tumor microenvironment, potentially regulating immune cell toxicity and lymphocytes infiltration. Moreover, TMCs 4-8 were correlated with tumor mutation burden and expression of PD-1/PD-L1/CTLA4 in 33 cancers. Thus, we established an immunotherapy response prediction (IRP) score based on the signature of TMCs 4-8. Patients with higher IRP scores showed higher immunotherapeutic responses in five cohorts of skin melanoma (area under curve [AUC] = 0.90 in the training cohort, AUCs range from 0.70 to 0.83 in the validation cohorts). Together, our study highlights the great potential of TMCs as biomarkers for prognosis and immunotherapeutic response, which can pave the way for further investigation of the tumor-infiltrating mechanisms and therapeutic potentials of TMCs in cancer.
Highlights
Cancer is a disease in cells with multi-omics dysregulations, such as genetic alterations, differential DNA methylations, and transcriptomic and metabolic disorders [1]
TMC4, TMC5, TMC6, TMC7, and TMC8 were widely expressed in diverse tissue types
Transmembrane Channel-like (TMC) were commonly associated with tumor mutation burdens (TMB), and expression of PD-1/PD-L1/CTLA4, which implied that TMCs may be of potential value in the prediction of immunotherapeutic response
Summary
Cancer is a disease in cells with multi-omics dysregulations, such as genetic alterations, differential DNA methylations, and transcriptomic and metabolic disorders [1]. Advances in highthroughput sequencing and bioinformatic technologies over the past decades have allowed millions of omics-level alterations to be detected, and made it possible to systematically study their roles in tumorigenesis and progression [2]. Most of the multi-omics alterations are not well understood. Millions of genetic mutations were detected in different cancer types, while their roles in immunotherapeutic response and tumor microenvironment were largely unknown, and their clinical potentials were not fully studied. A complete understanding of the omics-level alterations in different cancer types is essential to identify novel potential therapeutic targets and vulnerabilities
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