Abstract
Tumor mutation burden (TMB) and tumor infiltrating lymphocytes have been well-recognized as molecular determinants of immunotherapeutic responsiveness in many types of cancer. However, the relationship between TMB with immune infiltrates and their prognostic role are reported occasionally in skin cutaneous melanoma (SKCM). We obtained the somatic mutation data and transcriptome profiles of 454 SKCM patients from The Cancer Genome Atlas (TCGA) database, and analyzed the mutation profiles using “maftools” package. Correlation analysis revealed that lower TMB levels conferred poor survival outcomes, associated with lower age and advanced pathological stage. Differential analysis was conducted to the genome expression between two TMB groups using “limma” package, and we identified four hub TMB-related immune genes including CNTFR, CRABP2, GAL, and PAEP. We further analyzed the underlying relationships of the copy number variations (CNVs) of four hub genes with immune infiltrates in SKCM microenvironment through TIMER database. The results indicated that diverse forms of CNVs carried by hub genes could commonly inhibit immune infiltrates. Based on the CIBERSORT method, we compared the proportions of 22 immune cells in two TMB groups and assessed their prognostic value. The data revealed that infiltrations levels of regulatory T (Treg) cell and dendritic activated cells in high-TMB group were lower than that in low-TMB group, while M1 and M2 macrophages showed the opposite trend, especially the levels of neutrophil and macrophage correlated positively with prognosis of SKCM. Finally, we constructed a TMB Prognostic Index (TMBPI) to evaluate the predictive accuracy of the four hub TMB-related immune genes. The ROC curve was drawn to assess the predictive accuracy with AUC = 0.664 and higher TMBPI conferred poor survival outcomes, which warranted further investigation and larger samples to validate.
Highlights
Malignant melanoma is one of the most aggressive cancers, the incidence of which is rising worldwide [1,2,3]
We further evaluated the copy number variations (CNVs) of hub immune genes with immune infiltrates in skin cutaneous melanoma (SKCM) based on the “SCNA” module of TIMER database [28]
These mutations were further summarized in different groups, in which missense mutation accounts for the most fraction (Figure S1A), single nucleotide polymorphism occurred more frequently than deletion or insertion (Figure S1B), and C>T was the most common of single nucleotide variants in SKCM (Figure S1C)
Summary
Malignant melanoma is one of the most aggressive cancers, the incidence of which is rising worldwide [1,2,3]. On the basis of the anatomical location, melanoma is subdivided into three subtypes: skin cutaneous melanoma (SKCM), acral melanoma, and mucosal melanoma [4, 5]. Skin cutaneous melanoma (SKCM) is the major subtype of melanoma in Caucasians, which accounts for more than 90% [6]. Advances in immunotherapy have significantly improved survival outcomes of SKCM patients. The immune checkpoint blockade (ICB) targeting PD-1/PD-L1 and CTLA-4/B7-1 have been approved for the treatment of advanced SKCM by Food and Drug Administration (FDA) [8,9,10,11]. The overall efficacy rate of PD-1 blockade in SKCM is approximately 26 to 44% [8, 12], indicating more than 50% of SKCM patients are not suitable for ICB therapy. Identification and characterization of potential biomarkers and their application in combination with immunotherapy are urgently required
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