Comprehensive analysis of the prognosis, tumor microenvironment, and immunotherapy response of SDHs in colon adenocarcinoma

Abstract

Background: Succinate dehydrogenase (SDH), one of the key enzymes in the tricarboxylic acid cycle, is mainly found in the mitochondria. SDH consists of four subunits encoding SDHA, SDHB, SDHC, and SDHD. The biological function of SDH is significantly related to cancer progression. Colorectal cancer (CRC) is one of the most common malignant tumors globally, whose most common histological subtype is colon adenocarcinoma (COAD). However, the correlation between SDH factors and COAD remains unclear.

Methods: The data on pan-cancer was obtained from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis showed the prognostic ability of SDHs. The cBioPortal database reflected genetic variations of SDHs. The correlation analysis was conducted between SDHs and mitochondrial energy metabolism genes (MMGs) and the protein-protein interaction (PPI) network was built. Consequently, Univariate and Multivariate Cox Regression Analysis on SDHs and other clinical characteristics were conducted. A nomogram was established. The ssGSEA analysis visualized the association between SDHs and immune infiltration. Immunophenoscore (IPS) explored the correlation between SDHs and immunotherapy, and the correlation between SDHs and targeted therapy was investigated through Genomics of Drug Sensitivity in Cancer. Finally, qPCR and immunohistochemistry detected SDHs' expression.

Results: After assessing SDHs differential expression in pan-cancer, we found that SDHB, SDHC, and SDHD benefit COAD patients. The cBioPortal database demonstrated that SDHA was the top gene in mutation frequency rank. Correlation analysis mirrored a strong link between SDHs and MMGs. We formulated a nomogram and found that SDHB, SDHC, SDHD, and clinical characteristics correlated with COAD patients' survival. For T helper cells, Th2 cells, and Tem, SDHA, SDHB, SDHC, and SDHD were significantly enriched in the high expression group. Moreover, COAD patients with high SDHA expression were more suitable for immunotherapy. And COAD patients with different SDHs' expression have different sensitivity to targeted drugs. Further verifying the gene and protein expression levels of SDHs, we found that the tissues were consistent with the bioinformatics analysis.

Conclusions: Our study analyzed the expression and prognostic value of SDHs in COAD, explored the pathway mechanisms involved, and the immune cell correlations, indicating that SDHs might be biomarkers for COAD patients.

Keywords: colon adenocarcinoma (COAD); colorectal cancer; immune infiltration; immune treatment; prognostic; succinate dehydrogenase (SDH).