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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.
摘要：
介绍细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）是一种抑制致癌基因，在包括乳腺癌在内的各种类型的癌症中上调。肝脏,甲状腺，和胆管癌由于其在细胞周期调节和细胞分裂中的关键作用。然而，它主要是在基因水平上进行研究，但在泛癌症分析中作为生物标志物的研究仍然很少，这项研究显示了其显著的潜在诊断和预后特征。然而,本研究旨在探讨CDKN2A作为诊断和预后生物标志物在各种类型癌症中的作用,主要集中在结肠腺癌(COAD).方法我们在不同类型癌症的泛癌症分析中调查了CDKN2A基因表达，以通过使用各种生物信息学工具显示其诊断潜力特征。包括肿瘤免疫评估资源（TIMER）2.0，基因表达谱交互式分析（GEPIA），和阿拉巴马大学伯明翰癌症数据分析门户（UALCAN）数据库。TIMER用于对由从癌症基因组图谱（TCGA）获得的10,000个RNA-seq样品组成的32种癌症类型的基因表达进行分析，并分析肿瘤浸润免疫细胞。此外,GEPIA和UALCAN进一步用于分析基因表达，在基因调控方面，病理阶段，和临床参数，包括性别,年龄,和种族。因此,我们用了GEPIA,UALCAN,和Kaplan-Meier绘图仪，特别是在腺癌中，通过研究CDKN2A的高表达与患者的总体生存率的相关性来研究CDKN2A的预后，以显示肿瘤的进展。然后，我们通过使用cBio癌症基因组学门户（cBioPortal）研究了CDKN2A的遗传改变，包括10项泛癌症研究。我们通过使用基因表达综合（GEO）的公共队列来总结基因验证分析。结果CDKN2A在大多数癌症中呈上调趋势，在5种癌症中呈明显上调趋势。它们通常可以在三个数据库中识别，包括乳腺浸润性癌（p<0.001），肾发色（p<0.001），肾透明细胞癌（p<0.001），肾乳头状细胞癌（p<0.001），和COAD(p<0.001)。与致病阶段II和III相关的上调显着不同（pr（>F）=0.00234），这在COAD中比在其他癌症中更明显。该基因显示出与三种癌症患者生存预后不良相关的高上调，包括COAD(对数秩p=0.011)，间皮瘤（log-rankp=5.9e-07），和肝细胞癌（log-rankp=0.0045）。因此,COAD是唯一一种在CDKN2A高上调期间显示诊断和预后潜力特征的综合分析肿瘤。此外，CDKN2A以深度缺失（9％）的形式显示出罕见的突变，并显示出与CD4T细胞相关的上调（p=0.0108），巨噬细胞（p=0.0073），和嗜中性粒细胞(p=0.0272)作为免疫细胞浸润COAD。结论我们的研究证明了CDKN2A的泛癌症相关性，并揭示了显示CDKN2A的新颖性，强调了其作为COAD诊断预后生物标志物的潜力，因为CDKN2A主要在COAD的遗传水平上进行研究。
