Gene expression and immune infiltration in melanoma patients with different mutation burden

Liwei Wang,Lei Shi,Zhengjian Yan,Guosheng Zhao,Rui Liu,Fu Chen

doi:10.1186/s12885-021-08083-1

Abstract

BackgroundImmunotherapy is a vital component in cancer treatment. However, due to the complex genetic bases of cancer, a clear prediction index for efficacy has not been established. Tumor mutation burden (TMB) is one of the essential factors that affect immunotherapeutic efficacies, but it has not been determined whether the mutation is associated with the survival of Skin Cutaneous Melanoma (SKCM) patients. This study aimed at evaluating the correlation between TMB and immune infiltration.MethodsSomatic mutation profiles (n = 467), transcriptome data (n = 471), and their clinical information (n = 447) of all SKCM samples were downloaded from The Cancer Genome Atlas (TCGA) database. For each sample, TMB was calculated as the number of variants per megabase. Based on K-M survival analysis, they were allocated into the high-TMB and low-TMB groups (the optimal cutoff was determined by the ‘surv_cutpoint’ algorithm of survival R package). Then, Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) were performed, with immune-associated biological pathways found to be significantly enriched in the low-TMB group. Therefore, immune genes that were differentially expressed between the two groups were evaluated in Cox regression to determine their prognostic values, and a four-gene TMB immune prognostic model (TMB-IP) was constructed.ResultsElevated TMB levels were associated with better survival outcomes in SKCM patients. Based on the cutoff value in OS analysis, they were divided into high-TMB and low-TMB groups. GSEA revealed that the low-TMB group was associated with immunity while intersection analysis revealed that there were 38 differentially expressed immune-related genes between the two groups. Four TMB-associated immune genes were used to construct a TMB-IP model. The AUC of the ROC curve of this model reached a maximum of 0.75 (95%CI, 0.66–0.85) for OS outcomes. Validation in each clinical subgroup confirmed the efficacy of the model to distinguish between high and low TMB-IP score patients.ConclusionsIn SKCM patients, low TMB was associated with worse survival outcomes and enriched immune-associated pathways. The four TMB-associated immune genes model can effectively distinguish between high and low-risk patients.

Highlights

Immunotherapy is a vital component in cancer treatment
Mutation profiles in Skin Cutaneous Melanoma (SKCM) Somatic mutation profiles for 467 SKCM patients were retrieved from the The Cancer Genome Atlas (TCGA) database
Missense mutations were the most common (Fig. 1b), while deletion/insertion mutaions were common than single nucleotide polymorphisms (SNP) (Fig. 1c)

Summary

Introduction

Immunotherapy is a vital component in cancer treatment. due to the complex genetic bases of cancer, a clear prediction index for efficacy has not been established. Tumor mutation burden (TMB) is one of the essential factors that affect immunotherapeutic efficacies, but it has not been determined whether the mutation is associated with the survival of Skin Cutaneous Melanoma (SKCM) patients. Before 2011, the median survival time for metastatic melanoma patients was 9 months, but has been reported to exceed 2 years [8]. These improvements are mainly attributed to small molecule inhibitors (e.g., BRAF inhibitors, MEK inhibitors) [9, 10] and immune checkpoint blockade (ICB) [11,12,13]. Identification of CTLA-4 and PD-L1/PD-1 antibodies has enhanced advances in tumor immunotherapy [14, 15]

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