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. 2023 Aug 11;11(8):2254.
doi: 10.3390/biomedicines11082254.

Cyclin Dependent Kinase Inhibitor 2A Genetic and Epigenetic Alterations Interfere with Several Immune Components and Predict Poor Clinical Outcome

Mohamed A Soltan  1 , Ahmad A Alhanshani  2 , Ayed A Shati  2 , Youssef A Alqahtani  2 , Dalal Sulaiman Alshaya  3 , Jawaher Alharthi  4 , Sarah Awwadh Altalhi  4 , Eman Fayad  4 , Mohamed Samir A Zaki  5 , Refaat A Eid  6
Affiliations

Cyclin Dependent Kinase Inhibitor 2A Genetic and Epigenetic Alterations Interfere with Several Immune Components and Predict Poor Clinical Outcome

Mohamed A Soltan et al. Biomedicines. .

Abstract

Cyclin dependent kinase inhibitor 2A (CDKN2A) is a well-known tumor suppressor gene as it functions as a cell cycle regulator. While several reports correlate the malfunction of CDKN2A with the initiation and progression of several types of human tumors, there is a lack of a comprehensive study that analyzes the potential effect of CDKN2A genetic alterations on the human immune components and the consequences of that effect on tumor progression and patient survival in a pan-cancer model. The first stage of the current study was the analysis of CDKN2A differential expression in tumor tissues and the corresponding normal ones and correlating that with tumor stage, grade, metastasis, and clinical outcome. Next, a detailed profile of CDKN2A genetic alteration under tumor conditions was described and assessed for its effect on the status of different human immune components. CDKN2A was found to be upregulated in cancerous tissues versus normal ones and that predicted the progression of tumor stage, grade, and metastasis in addition to poor prognosis under different forms of tumors. Additionally, CDKN2A experienced different forms of genetic alteration under tumor conditions, a characteristic that influenced the infiltration and the status of CD8, the chemokine CCL4, and the chemokine receptor CCR6. Collectively, the current study demonstrates the potential employment of CDKN2A genetic alteration as a prognostic and immunological biomarker under several types of human cancers.

Keywords: CDKN2A; differential expression; epigenetic alteration; genetic alteration; immunotherapy; patient survival.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CDKN2A differential expression analysis and its interference with tumor stage, grade, and metastasis. (A) Differential expression of CDKN2A as analyzed by TIMER2.0 where blue represents normal, red represents tumor, and purple represents metastatic sample (**: p-value < 0.01; ***: p-value < 0.001) (B) GEPIA2 differential expression analysis of CDKN2A in tumors that lack a normal control on TIMER2.0 (*: p-value < 0.05). (C) Tumors experienced a positive correlation between CDKN2A levels and tumor stage. (D) Tumors experienced a positive correlation between CDKN2A levels and tumor grade. (E) Tumors experienced a consistent positive correlation between CDKN2A expression and tissue type (normal–tumor–metastatic).
Figure 2
Figure 2
(A) Tumors experienced significant upregulation of CDKN2A protein in tumor tissue versus control. (B) Tumors experienced significant downregulation of CDKN2A protein in tumor tissue versus control. (C,D) IHC samples showing weak or no stain for CDKN2A protein in tumor and normal samples, respectively where all samples are downloaded with 200 µm scale.
Figure 3
Figure 3
The correlation between CDKN2A expression and patient survival. (A) Disease-free survival. (B) Overall survival as assessed from the GEPIA2 database.
Figure 4
Figure 4
The correlation between CDKN2A expression and patient survival. (A) Overall survival. (B) Relapse-free survival as assessed from the KM plotter.
Figure 5
Figure 5
Mutation profile of CDKN2A as assessed by the cBioPortal web server. (A) The alteration frequency of CDKN2A in a panel of analyzed human cancers. (C) Forms of CDKN2A mutations. (B) A map for sites and types of CDKN2A mutations. (D) The 3D structure of CDKN2A, with a highlight on the most altered site. € Assessment of the correlation between CDKN2A mutation and disease-free, disease-specific, progression-free, and overall survival.
Figure 6
Figure 6
Differential methylation analysis of CDKN2A in tumor samples versus normal ones. (A) Analysis of CpG-aggregated methylation of CDKN2A. ns: p > 0.05; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001; ****: p ≤ 0.0001. (B) Tumors with CDKN2A promoter hypermethylation in tumor samples versus control.
Figure 7
Figure 7
(A) Heat map showing the correlation between CDKN2A deep deletion and CD8 infiltration. (B,C) Violin plots showing the correlation between CDKN2A deletion and CD8 infiltration in PAAD and HNSC, respectively.
Figure 8
Figure 8
Scatter plot showing the positive correlation between CDKN2A CNA and the expression of several immune checkpoints in (A) PAAD, (B) HNSC, (C) BLCA, and (D) LUSC.
Figure 9
Figure 9
Tumors that experienced a positive correlation between CDKN2A CNA and CCL4 expression.
Figure 10
Figure 10
Tumors that experienced a positive correlation between CDKN2A CNA and CCR6 expression.
Figure 11
Figure 11
CDKN2A network interactions. (A) Network of top 50 CDKN2A interacting proteins as determined by the STRING database. (B) Venn diagram demonstrating the intersection between CDKN2A interacting and correlating proteins. (C) Scatter plot showing the positive correlation between CDKN2A expression and the expression of (ASF1B, CDC20, MCM2, and RFC4) as determined by GEPIA2. (D) KEGG/GO enrichment analysis based on CDKN2A-binding and interacted genes.
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