A Comprehensive Pan-Cancer Analysis Reveals Cyclin-Dependent Kinase Inhibitor 2A Gene as a Potential Diagnostic and Prognostic Biomarker in Colon Adenocarcinoma

Our plain-English summary of A Comprehensive Pan-Cancer Analysis Reveals Cyclin-Dependent Kinase Inhibitor 2A Gene as a Potential Diagnostic and Prognostic Biomarker in Colon Adenocarcinoma, by A. Salem, S. Ahmed, M. Khalfallah, et al (Curēus, 2024).

The study

• Authors: A. Salem, S. Ahmed, M. Khalfallah, N. Hamadan, W. ElShikh, M. Alfaki
• Journal: Curēus
• Published: 2024;16(5):e60586
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a suppressor carcinogenic gene that is upregulated across various types of cancer including breast, liver, thyroid, and bile duct cancer due to its crucial role in cell cycle regulation and cell division. Nevertheless, it is mostly investigated at the genetic level, but it is still poorly studied on pan-cancer analysis as a biomarker and this study shows its significant potential diagnostic and prognostic characteristics. However, this study aims to investigate the role of CDKN2A as a diagnostic and prognostic biomarker across various types of cancer focusing primarily on colon adenocarcinoma (COAD). Methods We investigated CDKN2A gene expression in a pan-cancer analysis across different types of cancer to show its diagnostic potential characteristics by using various bioinformatic tools, including Tumor Immune Estimation Resource (TIMER) 2.0, Gene Expression Profiling Interactive Analysis (GEPIA), and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. TIMER was used to profile gene expression across 32 types of cancer composed of 10,000 RNA-seq samples obtained from the Cancer Genome Atlas (TCGA) and to analyze the tumor-infiltrating immune cells. In addition, GEPIA and UALCAN were further used to analyze gene expression, in terms of gene regulation, pathological stages, and clinical parameters, including gender, age, and race. Therefore, we used GEPIA, UALCAN, and Kaplan-Meier plotter particularly across adenocarcinoma to investigate CDKN2A prognosis by studying its high expression association with the patient's overall survival rate to show the tumor progression. Then, we looked into the genetic alteration of CDKN2A by using the cBio Cancer Genomics Portal (cBioPortal), including 10 pan-cancer studies. We concluded the analysis with gene validation by using a public cohort in Gene Expression Omnibus (GEO). Results CDKN2A showed a trend of upregulation in most cancers and it was significantly upregulated in five cancers, which were commonly identifiable in three databases, including breast invasive carcinoma (p < 0.001), kidney chromophobe (p < 0.001), kidney renal clear cell carcinoma (p < 0.001), kidney renal papillary cell carcinoma (p < 0.001), and COAD (p < 0.001). The upregulation was significantly different in association with pathogenic stages II and III (pr(>F) = 0.00234) which was identifiable significantly in COAD more than in other cancers. The gene showed a high upregulation in association with poor prognosis of patient survival in three cancers, including COAD (log-rank p = 0.011), mesothelioma (log-rank p = 5.9e-07), and liver hepatocellular carcinoma (log-rank p = 0.0045). Therefore, COAD was the only comprehensively analyzed tumor to show a diagnostic and prognostic potential characteristic during high upregulation of CDKN2A. Furthermore, CDKN2A displayed a rare mutation in the form of deep deletion (9%) and revealed an upregulation associated with CD4+ T cells (p = 0.0108), macrophage (p = 0.0073), and neutrophils (p = 0.0272) as immune cells infiltrating COAD. Conclusion Our study demonstrates the pan-cancer relevance of CDKN2A and revealed a novelty in showing CDKN2A underscores its potential as a diagnostic prognostic biomarker in COAD since CDKN2A is mostly studied at a genetic level across COAD.

Copyright © 2024, Salem et al.

In plain English

This study was a computer analysis of public cancer gene databases. It involved no new patients or tissue and did not study asbestos exposure. The authors compared how active the CDKN2A gene was in tumor versus normal tissue across about 32 cancer types, using The Cancer Genome Atlas and several online tools, with a focus on colon adenocarcinoma. CDKN2A was more active in tumor tissue in 14 cancer types in all three tools compared. In one tool, higher activity was associated with poorer overall survival in colon adenocarcinoma (p = 0.011), mesothelioma (p = 5.9 times 10 to the minus 7) and liver hepatocellular carcinoma (p = 0.0045). A further colon cancer survival analysis reported a hazard ratio of 1.6. However, the text states that patients with lower gene activity had lower survival (92.77 months) than those with higher activity (145 months). A small public colon cancer dataset (nine tumor and six normal samples) also showed higher CDKN2A activity. The authors concluded CDKN2A is a potential biomarker in colon adenocarcinoma and said laboratory validation is still needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: computational (bioinformatics) analysis of public gene-expression and genomic databases; no human participants or tissue
• Who was studied: Public data: about 10,000 RNA-seq tumor and normal samples covering 32 cancer types from The Cancer Genome Atlas (TCGA) via TIMER 2.0, plus GEPIA and UALCAN data. Survival data on 1061 colon cancer patients from the Kaplan-Meier plotter. 76,639 samples from 75,661 patients in 10 cBioPortal studies. A GEO dataset (GSE84984) of nine colon tumor biopsies and six adjacent normal mucosa biopsies.
• Exposure: No asbestos or other fiber exposure was studied. The variable examined was expression (activity) and alteration of the CDKN2A gene.
• Main results:
  • Comparing TIMER, GEPIA and UALCAN, CDKN2A was upregulated in tumor tissue in 14 cancer types common to all three tools, including colon adenocarcinoma (COAD).
  • In GEPIA, high CDKN2A expression was associated with overall survival in mesothelioma (MESO, p = 5.9x10-7), pheochromocytoma and paraganglioma (PCPG, p = 0.016) and liver hepatocellular carcinoma (LIHC, p = 0.0045), as well as COAD (p = 0.011).
  • In UALCAN, high expression was associated with survival in COAD (p = 0.031), LIHC (p = 0.014), MESO (p = 0.0099) and PCPG (p = 0.068).
  • In the Kaplan-Meier plotter colon cancer analysis, survival differed between low and high CDKN2A expression groups (log-rank p = 6.3e-6, hazard ratio 1.6). The text states that patients with lower expression had lower overall survival (92.77 months) than those with higher expression (145 months).
  • In 10 cBioPortal pan-cancer studies, CDKN2A was altered in 9% of queried samples (6770), with deep deletion described as the mutation type.
  • In COAD, CDKN2A expression was positively and significantly correlated with infiltration of CD4+ T cells (p = 0.0108), macrophages (p = 0.0073) and neutrophils (p = 0.0272).
  • In the GEO colon cancer dataset GSE84984, CDKN2A was upregulated in tumor versus normal samples (adjusted p-value 0.000564, logFC 0.5351).
• The authors' conclusion: The authors concluded that CDKN2A's differential expression, its association with poor survival, its genetic alterations and its link to immune cell infiltration point to its potential as a biomarker in colon adenocarcinoma.
• Limitations the authors state:
  • The analysis relied only on public computational databases, and the authors state that wet-lab validation is needed to clarify the gene's role and therapeutic implications.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Adenocarcinoma, CDKN2A, Carcinogenic, Prognosis, Overall Survival, Carcinoma, Mesothelioma.

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