This study aims to investigate the expression variation, biological significance, and prognostic value of cyclin-dependent kinase inhibitor 2A (CDKN2A) as a common biomarker across 33 malignancies. Various bioinformatics tools, including UALCAN, GEPIA2, OncoDB, cBioPortal, TIMER2, STRING, DAVID, and the GSCA database, were employed for this pan-cancer analysis. The results revealed significant up-regulation of CDKN2A in 24 major human cancer subtypes (P < 0.05). This up-regulation was strongly associated with poor overall survival and tumor dissemination, particularly in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and liver hepatocellular carcinoma (LIHC), highlighting its potential as a prognostic biomarker. Moreover, CDKN2A overexpression was linked to diverse clinicopathological characteristics of patients. Genetic alterations recorded via cBioPortal indicated minimal mutation rates in COAD, LIHC, and UCEC. Additionally, promoter methylation, drug sensitivity, and enrichment analyses were performed to explore associations with CDKN2A expression. Overall, the findings emphasize the potential of CDKN2A as a shared diagnostic and prognostic biomarker, as well as a therapeutic target in COAD, LIHC, and UCEC, particularly in patients with varied clinicopathological traits.
Ekwomadu T, Mwanza M, Musekiwa A, 2022, Mycotoxin-Linked Mutations and Cancer Risk: A Global Health Issue. Int J Environ Res Public Health, 19(13): 7754. https://doi.org/10.3390/ijerph19137754
Sial N, Saeed S, Ahmad M, et al., 2021, Multi-Omics Analysis Identified TMED2 as a Shared Potential Biomarker in Six Subtypes of Human Cancer. Int J Gen Med, 14: 7025–7042. https://doi.org/10.2147/IJGM.S327367
Trapani D, Ginsburg O, Fadelu T, et al., 2022, Global Challenges and Policy Solutions in Breast Cancer Control. Cancer Treat Rev, 104: 102339. https://doi.org/10.1016/j.ctrv.2022.102339
Zhu X, Tang L, Mao J, et al., 2022, Decoding the Mechanism behind the Pathogenesis of the Focal Segmental Glomerulosclerosis. Comput Math Methods Med, 2022: 1941038. https://doi.org/10.1155/2022/1941038. Retraction in Comput Math Methods Med, 2023: 9812513. https://doi.org/10.1155/2023/9812513
Marzagalli M, Fontana F, Raimondi M, et al., 2021, Cancer Stem Cells-Key Players in Tumor Relapse. Cancers (Basel), 13(3): 376. https://doi.org/10.3390/cancers13030376
Black JRM, McGranahan N, 2021, Genetic and Non-Genetic Clonal Diversity in Cancer Evolution. Nat Rev Cancer, 21(6): 379–392. https://doi.org/10.1038/s41568-021-00336-2
Bray F, Laversanne M, Sung H, et al., 2024, Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 countries. CA Cancer J Clin, 74(3): 229–263. https://doi.org/10.3322/caac.21834
Siegel RL, Miller KD, Jemal A, 2018, Cancer Statistics, 2018. CA Cancer J Clin, 68(1): 7–30. https://doi.org/10.3322/caac.21442
Mbemi A, Khanna S, Njiki S, et al., 2020, Impact of Gene-Environment Interactions on Cancer Development. Int J Environ Res Public Health, 17(21): 8089. https://doi.org/10.3390/ijerph17218089
Tzenois N, 2023, Obesity as a Risk Factor for Cancer. EPRA International Journal of Research & Development, 8(2): 101–104. https://doi.org/10.36713/epra12423
Klein AP, 2021, Pancreatic Cancer Epidemiology: Understanding the Role of Lifestyle and Inherited Risk Factors. Nat Rev Gastroenterol Hepatol, 18(7): 493–502. https://doi.org/10.1038/s41575-021-00457-x
Volkel V, Hueting TA, Draeger T, et al., 2021, Improved Risk Estimation of Locoregional Recurrence, Secondary Contralateral Tumors and Distant Metastases in Early Breast Cancer: The INFLUENCE 2.0 Model. Breast Cancer Res Treat, 189(3): 817–826. https://doi.org/10.1007/s10549-021-06335-z
Akcay M, Etiz D, Celik O, 2020, Prediction of Survival and Recurrence Patterns by Machine Learning in Gastric Cancer Cases Undergoing Radiation Therapy and Chemotherapy. Adv Radiat Oncol, 5(6): 1179–1187. https://doi.org/10.1016/j.adro.2020.07.007
Aramini B, Masciale V, Grisendi G, et al., 2022, Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel), 14(4): 976. https://doi.org/10.3390/cancers14040976
Adib E, Nassar AH, Akl EW, et al., 2021, CDKN2A Alterations and Response to Immunotherapy in Solid Tumors. Clin Cancer Res, 27(14): 4025–4035. https://doi.org/10.1158/1078-0432.CCR-21-0575
Zhao R, Choi BY, Lee MH, et al., 2016, Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer. EBioMedicine, 8: 30–39. https://doi.org/10.1016/j.ebiom.2016.04.017
Wander SA, Cohen O, Gong X, et al., 2020, The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer. Cancer Discov, 10(8): 1174–1193. https://doi.org/10.1158/2159-8290.CD-19-1390
Gao X, Leone GW, Wang H, 2020, Cyclin D-CDK4/6 Functions in Cancer. Adv Cancer Res, 148: 147–169. https://doi.org/10.1016/bs.acr.2020.02.002
Ming Z, Lim SY, Rizos H, 2020, Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression. Biomolecules, 10(10): 1447. https://doi.org/10.3390/biom10101447
Louis DN, Perry A, Wesseling P, et al., 2021, The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary. Neuro Oncol, 23(8): 1231–1251. https://doi.org/10.1093/neuonc/noab106
Zschernack V, Andreiuolo F, Dorner E, et al., 2024, p16 Immunohistochemistry as a Screening Tool for Homozygous CDKN2A Deletions in CNS Tumors. Am J Surg Pathol, 48(1): 46–53. https://doi.org/10.1097/PAS.0000000000002148
Guyot A, Duchesne M, Robert S, et al., 2019, Analysis of CDKN2A Gene Alterations in Recurrent and Non-Recurrent Meningioma. J Neurooncol, 145(3): 449–459. https://doi.org/10.1007/s11060-019-03333-6
Yuile A, Satgunaseelan L, Wei JQ, et al., 2023, CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review. Curr Issues Mol Biol, 45(7): 5276–5292. https://doi.org/10.3390/cimb45070335
Ahmad SU, Ali Y, Jan Z, et al., 2023, Computational Screening and Analysis of Deleterious nsSNPs in Human p14ARF (CDKN2A Gene) Protein Using Molecular Dynamic Simulation Approach. J Biomol Struct Dyn, 41(9): 3964–3975. https://doi.org/10.1080/07391102.2022.2059570
Zocchi L, Lontano A, Merli M, et al., 2021, Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management. J Clin Med, 10(16): 3760. https://doi.org/10.3390/jcm10163760
Kimura H, Klein AP, Hruban RH, et al., 2021, The Role of Inherited Pathogenic CDKN2A Variants in Susceptibility to Pancreatic Cancer. Pancreas, 50(8): 1123–1130. https://doi.org/10.1097/MPA.0000000000001888
Chan SH, Chiang J, Ngeow J, 2021, CDKN2A Germline Alterations and the Relevance of Genotype-Phenotype Associations in Cancer Predisposition. Hered Cancer Clin Pract, 19(1): 21. https://doi.org/10.1186/s13053-021-00178-x
Aftab A, Shahzad S, Hussain HMJ, et al., 2019, CDKN2A/P16INK4A Variants Association with Breast Cancer and Their In-Silico Analysis. Breast Cancer, 26(1): 11–28. https://doi.org/10.1007/s12282-018-0894-0
Zhang D, Wang T, Zhou Y, et al., 2023, Comprehensive Analyses of Cuproptosis-Related Gene CDKN2A on Prognosis and Immunologic Therapy in Human Tumors. Medicine (Baltimore), 102(14): e33468. https://doi.org/10.1097/MD.0000000000033468
Chen Z, Guo Y, Zhao D, et al., 2021, Comprehensive Analysis Revealed that CDKN2A is a Biomarker for Immune Infiltrates in Multiple Cancers. Front Cell Dev Biol, 9: 808208. https://doi.org/10.3389/fcell.2021.808208
Wang JZ, Patil V, Liu J, et al., 2023, Increased mRNA Expression of CDKN2A is a Transcriptomic Marker of Clinically Aggressive Meningiomas. Acta Neuropathol, 146(1): 145–162. https://doi.org/10.1007/s00401-023-02571-3. Erratum in Acta Neuropathol, 146(1): 171–172. https://doi.org/10.1007/s00401-023-02584-y
Chandrashekar DS, Karthikeyan SK, Korla PK, et al., 2022, UALCAN: An Update to the Integrated Cancer Data Analysis Platform. Neoplasia, 25: 18–27. https://doi.org/10.1016/j.neo.2022.01.001
Tang Z, Kang B, Li C, et al., 2019, GEPIA2: An Enhanced Web Server for Large-Scale Expression Profiling and Interactive Analysis. Nucleic Acids Res, 47(W1): W556–W560. https://doi.org/10.1093/nar/gkz430
Tang G, Cho M, Wang X, 2022, OncoDB: An Interactive Online Database for Analysis of Gene Expression and Viral Infection in Cancer. Nucleic Acids Res, 50(D1): D1334–D1339. https://doi.org/10.1093/nar/gkab970
De Bruijn I, Kundra R, Mastrogiacomo B, et al., 2023, Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal. Cancer Res, 83(23): 3861–3867. https://doi.org/10.1158/0008-5472.CAN-23-0816
Li T, Fu J, Zeng Z, et al., 2020, TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells. Nucleic Acids Res, 48(W1): W509–W514. https://doi.org/10.1093/nar/gkaa407
Szklarczyk D, Gable AL, Lyon D, et al., 2019, STRING v11: Protein-Protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets. Nucleic Acids Res, 47(D1): D607–D613. https://doi.org/10.1093/nar/gky1131
Sherman BT, Hao M, Qiu J, et al., 2022, DAVID: A Web Server for Functional Enrichment Analysis and Functional Annotation of Gene Lists (2021 Update). Nucleic Acids Res, 50(W1): W216–W221. https://doi.org/10.1093/nar/gkac194
Liu CJ, Hu FF, Xie GY, et al., 2023, GSCA: An Integrated Platform for Gene Set Cancer Analysis at Genomic, Pharmacogenomic and Immunogenomic Levels. Brief Bioinform, 24(1): bbac558. https://doi.org/10.1093/bib/bbac558
Nishiyama A, Nakanishi M, 2021, Navigating the DNA Methylation Landscape of Cancer. Trends Genet, 37(11): 1012–1027. https://doi.org/10.1016/j.tig.2021.05.002
Mattei AL, Bailly N, Meissner A, 2022, DNA Methylation: A Historical Perspective. Trends Genet, 38(7): 676–707. https://doi.org/10.1016/j.tig.2022.03.010
Clague MJ, Urbe S, Komander D, 2019, Breaking the Chains: Deubiquitylating Enzyme Specificity Begets Function. Nat Rev Mol Cell Biol, 20(6): 338–352. https://doi.org/10.1038/s41580-019-0099-1. Erratum in Nat Rev Mol Cell Biol, 20(5): 321. https://doi.org/10.1038/s41580-019-0112-8
Saleh R, Toor SM, Sasidharan Nair V, et al., 2020, Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression. Front Immunol, 11: 1469. https://doi.org/10.3389/fimmu.2020.01469
Pissa M, Helkkula T, Appelqvist F, et al., 2021, CDKN2A Genetic Testing in Melanoma-Prone Families in Sweden in the Years 2015–2020: Implications for Novel National Recommendations. Acta Oncol, 60(7): 888–896. https://doi.org/10.1080/0284186X.2021.1914346
Cao Z, Wei L, Zhu W, et al., 2018, Meta-Analysis of CDKN2A Methylation to Find Its Role in Prostate Cancer Development and Progression, and Also to Find the Effect of CDKN2A Expression on Disease-Free Survival (PRISMA). Medicine (Baltimore), 97(12): e0182. https://doi.org/10.1097/MD.0000000000010182
Sargen MR, Calista D, Elder DE, et al., 2020, Histologic Features of Melanoma Associated with Germline Mutations of CDKN2A, CDK4, and POT1 in Melanoma-Prone Families from the United States, Italy, and Spain. J Am Acad Dermatol, 83(3): 860–869. https://doi.org/10.1016/j.jaad.2020.03.100
Lin JC, Liu TP, Yang PM, 2020, CDKN2A-Inactivated Pancreatic Ductal Adenocarcinoma Exhibits Therapeutic Sensitivity to Paclitaxel: A Bioinformatics Study. J Clin Med, 9(12): 4019. https://doi.org/10.3390/jcm9124019
Worst TS, Weis CA, Stohr R, et al., 2018, CDKN2A as Transcriptomic Marker for Muscle-Invasive Bladder Cancer Risk Stratification and Therapy Decision-Making. Sci Rep, 8(1): 14383. https://doi.org/10.1038/s41598-018-32569-x
Deneka AY, Baca Y, Serebriiskii IG, et al., 2022, Association of TP53 and CDKN2A Mutation Profile with Tumor Mutation Burden in Head and Neck Cancer. Clin Cancer Res, 28(9): 1925–1937. https://doi.org/10.1158/1078-0432.CCR-21-4316
Hawe JS, Wilson R, Schmid KT, et al., 2022, Genetic Variation Influencing DNA Methylation Provides Insights into Molecular Mechanisms Regulating Genomic Function. Nat Genet, 54(1): 18–29. https://doi.org/10.1038/s41588-021-00969-x
Rauluseviciute I, Drablos F, Rye MB, 2020, DNA Hypermethylation Associated with Upregulated Gene Expression in Prostate Cancer Demonstrates the Diversity of Epigenetic Regulation. BMC Med Genomics, 13(1): 6. https://doi.org/10.1186/s12920-020-0657-6
Geng R, Zheng Y, Zhao L, et al., 2020, RNF183 Is a Prognostic Biomarker and Correlates With Tumor Purity, Immune Infiltrates in Uterine Corpus Endometrial Carcinoma. Front Genet, 11: 595733. https://doi.org/10.3389/fgene.2020.595733
Cui X, Zhang X, Liu M, et al., 2020, A Pan-Cancer Analysis of the Oncogenic Role of Staphylococcal Nuclease Domain-Containing Protein 1 (SND1) in Human Tumors. Genomics, 112(6): 3958–3967. https://doi.org/10.1016/j.ygeno.2020.06.044
Poon RYC, 2021, Cell Cycle Control: A System of Interlinking Oscillators. Methods Mol Biol, 2329: 1–18. https://doi.org/10.1007/978-1-0716-1538-6_1
Matthews HK, Bertoli C, de Bruin RAM, 2022, Cell Cycle Control in Cancer. Nat Rev Mol Cell Biol, 23(1): 74–88. https://doi.org/10.1038/s41580-021-00404-3
Wang Z, 2021, Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling. Cells, 10(12): 3327. https://doi.org/10.3390/cells10123327
Liu J, Peng Y, Wei W, 2022, Cell Cycle on the Crossroad of Tumorigenesis and Cancer Therapy. Trends Cell Biol, 32(1): 30–44. https://doi.org/10.1016/j.tcb.2021.07.001
Sun Y, Liu Y, Ma X, et al., 2021, The Influence of Cell Cycle Regulation on Chemotherapy. Int J Mol Sci, 22(13): 6923. https://doi.org/10.3390/ijms22136923