Identification of Novel Molecular Therapeutic Targets and Their Potential Prognostic Biomarkers Based on Cytolytic Activity in Skin Cutaneous Melanoma.

Haoxue Zhang,Shengxiu Liu,Yuyao Liu,Delin Hu

doi:10.3389/fonc.2022.844666

Abstract

Skin cutaneous melanoma (SKCM) attracts attention worldwide for its extremely high malignancy. A novel term cytolytic activity (CYT) has been introduced as a potential immunotherapy biomarker associated with counter-regulatory immune responses and enhanced prognosis in tumors. In this study, we extracted all datasets of SKCM patients, namely, RNA sequencing data and clinical information from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database, conducted differential expression analysis to yield 864 differentially expressed genes (DEGs) characteristic of CYT and used non-negative matrix factorization (NMF) method to classify molecular subtypes of SKCM patients. Among all genes, 14 hub genes closely related to prognosis for SKCM were finally screen out. Based on these genes, we constructed a 14-gene prognostic risk model and its robustness and strong predictive performance were further validated. Subsequently, the underlying mechanisms in tumor pathogenesis and prognosis have been defined from a number of perspectives, namely, tumor mutation burden (TMB), copy number variation (CNV), tumor microenvironment (TME), infiltrating immune cells, gene set enrichment analysis (GSEA) and immune checkpoint inhibitors (ICIs). Furthermore, combined with GTEx database and HPA database, the expression of genes in the model was verified at the transcriptional level and protein level, and the relative importance of genes in the model was described by random forest algorithm. In addition, the model was used to predict the difference in sensitivity of SKCM patients to chemotherapy and immunotherapy. Finally, a nomogram was constructed to better aid clinical diagnosis.

Highlights

Skin cutaneous melanoma (SKCM) is one of the most lethiferous malignancies
According to the median value of cytolytic activity (CYT), we separated all SKCM patients into a high-CYT and a low-CYT group, in which we conducted KM survival analysis, and the results indicated that the high-CYT group had better prognosis
Univariate Cox regression analysis told us that CYT was a protective factor validated in 3 independent datasets, and the conclusion came that the higher CYT, the better prognosis for SKCM patients (Figure 2A)

Summary

Introduction

Skin cutaneous melanoma (SKCM) is one of the most lethiferous malignancies. Though SKCM only constitutes ~5% of all skin cancers, it accounts for >75% of skin cancer deaths [1]. Most melanomas are removed via the standard surgical technique that excises both the tumor and a margin of normal appearing skin [2]. Surgical resection offers so little in the management of individuals with regional or distant metastases [3]. Adjuvant therapies, such as radiotherapy, immunotherapy, biochemotherapy, can possibly benefit postoperative patients [4]. Immunotherapy has promised an optimizing future for SKCM in recent years [6–8], managing to enhance the prognosis of SKCM patients. Though it has shown great clinical effect, only a small percentage of patients profit by long-range treatment [9]. Establishment of an efficient prognosis model is essential, and it can direct clinical treatment of SKCM patients

Methods

Results

Conclusion