Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase (cGAS) could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on cGAS gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of cGAS in malignant tumors.

cGAS expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate cGAS expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes.

Compared to normal tissues, cGAS was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). cGAS expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of cGAS genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with cGAS expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in cGAS expression in vitro. Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. According to the evidence presented above, cGAS may become an important target for cancer therapy.

This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS, making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.