Comprehensive analyses of cuproptosis-related gene CDKN2A on prognosis and immunologic therapy in human tumors

Abstract

Recent studies have identified a novel programmed cell death based on copper, named cuproptosis. However, as an anti-cuproptosis gene, the functional roles, definite mechanisms and prognostic value of CDKN2A in pan-cancer are largely unclear. The GEPIA2, cancer genome atlas (TCGA), the tumor immune estimation resource 2.0 and CPTAC databases were performed to validate the differential expression of CDKN2A in 33 tumors. The clinical features and survival prognosis analysis were conducted by GEPIA2 and UALCAN web tool. Genetic alteration analysis of CDKN2A in pan-cancer was also evaluated. Furthermore, the functional roles of CDKN2A were explored via DNA methylation analysis, tumor microenvironment, infiltration of immune cells, enrichment analysis and gene co-expression associated with cuproptosis and immune regulation. The CDKN2A expression, both at the transcriptional and translational level, was obviously upregulated in most cancer patients, which might lead to poor survival in certain cancer types. CDKN2A expression was significantly associated with tumor pathological stages in some cancer types. In adrenocortical carcinoma (ACC) and kidney renal clear cell carcinoma (KIRC), DNA methylation of CDKN2A was explored to induce poor clinical outcomes. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis indicated that CDKN2A expression was closely related to several cancer-associated signaling pathways, such as the p53 signaling pathway, Cellular senescence, DNA replication and Cell cycle signaling pathways. Gene set enrichment analysis (GSEA) analysis suggested that aberrantly expressed CDKN2A took part in the cell cycle regulation, immune regulation and mitochondrial signaling pathways in certain cancer patients. In addition, aberrant CDKN2A expression was closely correlated to immune infiltration and the levels of immune-regulatory genes. The study deeply defined the concrete roles of cuproptosis-related gene CDKN2A in tumorigenesis. The results provided new insights and pieces of evidence for treatment.

Anoikis-related gene CDKN2A predicts prognosis and immune response and mediates proliferation and migration in thyroid carcinoma

“…Promoter hypermethylation of the CDKN2A gene has been suspected to be associated with carcinogenicity in colorectal cancer, and CDKN2A methylation status in primary colorectal cancer was found to be a prognostic factor in colorectal cancer by analyzing CDKN2A methylation status in primary colorectal cancer using real-time methylation-specific PCR [29] . CDKN2A as a cuproptosis-related gene has also been comprehensively prognostic and immunologically studied in human tumors; CDKN2A expression is significantly upregulated in most cancer patients at the transcription and translation levels, CDKN2A expression is significantly correlated with tumor pathological staging of certain cancer types, the study further illustrates the role of CDKN2A in cancer development and development, which can provide certain research ideas for cancer treatment [30] . CDKN2A was also found to be an independent prognostic gene, and then we verified the prognostic function of CDKN2A through basic experiments.…”

Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer

“…The encoded proteins exert their tumor-suppressive effects by inhibiting cell-cycle progression through binding and inhibiting cyclin-dependent kinases CDK4/6. This interaction maintains the retinoblastoma (Rb) protein in an active state, preventing G1 to S phase transition [109][110][111]. Additionally, CDKN2A promotes apoptosis and senescence and inhibits cancer-associated processes like cell-in-cell structure formation and anchorage-independent growth, while it modulates antitumor immunity by influencing immune-cell infiltration [38,58,109,111].…”

Copper homeostasis and cuproptosis in cancer immunity and therapy

“…CDKN2A is overexpressed in most cancer patients, and associates with undesirable prognostic outcomes 63 . Among all cuproptosis‐related genes, CDKN2A has the highest mutation frequency (~49%) in pan‐cancer 64 .…”

“…CDKN2A is overexpressed in most cancer patients, and associates with undesirable prognostic outcomes. 63 Among all cuproptosisrelated genes, CDKN2A has the highest mutation frequency (~49%) in pan-cancer. 64 Experimentally, CDKN2A facilitates proliferative and migrative capacities as well as attenuates cuproptosis of HCC cells.…”