DNA damage repair-related gene signature predicts prognosis and indicates immune cell infiltration landscape in skin cutaneous melanoma

Abstract

Background: DNA damage repair plays an important role in the onset and progression of cancers and its resistance to treatment therapy. This study aims to assess the prognostic potential of DNA damage repair markers in skin cutaneous melanoma (SKCM).

Method: In this study, we have analyzed the gene expression profiles being downloaded from TCGA, GTEx, and GEO databases. We sequentially used univariate and LASSO Cox regression analyses to screen DNA repair genes associated with prognosis. Then, we have conducted a multivariate regression analysis to construct the prognostic profile of DNA repair-related genes (DRRGs). The risk coefficient is used to calculate the risk scores and divide the patients into two cohorts. Additionally, we validated our prognosis model on an external cohort as well as evaluated the link between immune response and the DRRGs prognostic profiles. The risk signature is compared to immune cell infiltration, chemotherapy, and immune checkpoint inhibitors (ICIs) treatment.

Results: An analysis using LASSO-Cox stepwise regression established a prognostic signature consisting of twelve DRRGs with strong predictive ability. Disease-specific survival (DSS) is found to be lower among high-risk patients group as compared to low-risk patients. The signature may be employed as an independent prognostic predictor after controlling for clinicopathological factors, as demonstrated by validation on one external GSE65904 cohort. A strong correlation is also found between the risk score and the immune microenvironment, along with the infiltrating immune cells, and ICIs key molecules. The gene enrichment analysis results indicate a wide range of biological activities and pathways to be exhibited by high-risk groups. Furthermore, Cisplatin exhibited a considerable response sensitivity in low-risk groups as opposed to the high-risk incidents, while docetaxel exhibited a considerable response sensitivity in high-risk groups.

Conclusions: Our findings provide a thorough investigation of DRRGs to develop an DSS-related prognostic indicator which may be useful in forecasting SKCM progression and enabling more enhanced clinical benefits from immunotherapy.

Keywords: DNA damage repair; immunotherapy; prognostic factor; skin cutaneous melanoma; tumor microenvironment.