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Development and Validation of a Novel Epigenetic-Related Prognostic Signature and Candidate Drugs for Patients with Lung Adenocarcinoma

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Development and Validation of a Novel Epigenetic-Related Prognostic Signature and Candidate Drugs for Patients with Lung Adenocarcinoma www.aging-us.com AGING 2021, Vol. 13, No. 14 Research Paper Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma Zhihao Wang1, Kidane Siele Embaye1, Qing Yang2, Lingzhi Qin1, Chao Zhang1, Liwei Liu1, Xiaoqian Zhan1, Fengdi Zhang3, Xi Wang1, Shenghui Qin1 1Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2Department of Pharmacy, Hiser Medical Center of Qingdao, Qingdao 266033, China 3Department of Pathology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430030, China Correspondence to: Shenghui Qin; email: [email protected] Keywords: lung adenocarcinoma, epigenetic-related genes, drugs, prognostic, TCGA Received: November 9, 2020 Accepted: May 11, 2021 Published: July 20, 2021 Copyright: © 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients. Results: Five epigenetic-related genes (ERGs) (ARRB1, PARP1, PKM, TFDP1, and YWHAZ) were identified as prognostic hub genes and used to establish a prognostic signature. According our risk score system, LUAD patients were stratified into high and low risk groups, and patients in the high risk group had a worse prognosis. ROC analysis indicated that the signature was precise in predicting the prognosis. A new nomogram was constructed based on the five hub genes, which can predict the OS of every LUAD patients. The calibration curves showed that the nomogram had better accuracy in prediction. Finally, candidate drugs that aimed at hub ERGs were identified, which included 47 compounds. Conclusions: Our epigenetic-related signature nomogram can effectively and reliably predict OS of LUAD patients, also we provide precise targeted chemotherapeutic drugs. Methods: The genomic data and clinical data of LUAD cohort were downloaded from the TCGA database and ERGs were obtained from the EpiFactors database. GSE31210 and GSE50081 microarray datasets were included as independent external datasets. Univariate Cox, LASSO regression, and multivariate Cox analyses were applied to construct the epigenetic-related signature. INTRODUCTION molecularly targeted therapies have been developed that caused significant improvement in the treatment of Lung cancer, which including two main types small cell LUAD, especially for patients with EGFR mutation [5] lung cancer (SCLC) and non–small cell lung cancer and ALK mutation [6, 7]. However, because of high (NSCLC), is the most common cause of cancer deaths in gene mutation heterogeneity and complexity in the world [1]. NSCLC accounts for ~85% of lung cancer molecular patterns of LUAD, large amount of LUAD diagnoses and imposes a heavy burden on global health patients without EGFR and ALK mutations lose the systems [2, 3]. Lung adenocarcinoma (LUAD) is the opportunity to use effective therapeutic drugs. Therefore, most common pathological subtype of NSCLC. Despite it is essential to identify reliable diagnostic and great advances in the treatment of LUAD, the clinical prognostic biomarkers for LUAD patients and thereby outcome is not satisfactory [4]. Recently, a number of provide precise targeted therapies. www.aging-us.com 18701 AGING Epigenetic regulation is broadly defined as repression or KEGG analysis results demonstrated that 91 ERGs were activation of gene expression via DNA methylation and mainly enriched in 4 pathways including homologous histone modification, without introducing changes in the recombination, cell cycle, lysine degradation and fanconi DNA sequence per se [8, 9]. Epigenetic dysregulation is anemia (Figure 2C, 2D). considered as an essential hallmark in the initiation and progression of different types of cancers [10, 11]. Identification of survival-related differentially Recently, epigenetic dysregulation has been reported to expressed ERGs promote carcinogenesis of pulmonary epithelial cells and the progression of LUAD [12]. Epigenetic genes, such as By using univariate Cox regression analysis, we DNMT, HDAC, and PARP1 have emerged as attractive identified 16 ERGs that were significantly associated targets for the development of anticancer drugs for with prognosis in patients with LUAD (Table 1) NSCLC [13–15]. Hence, epigenetic alterations are (P<0.05; Figure 3A). Of the 16 genes, 14 were considered to be an important characteristic in NSCLC identified as risk factors and two were identified as development and progression. Although, numerous protective factors. UHRF1, HJURP, BUB1, PBK, studies have reported prognostic signature for LUAD AURKA, ACTL6A, ASF1B, PRKDC, CDK1, PARP1, [16–19], only a few researchers have explored the role of UBE2T, YWHAZ, PKM, and TFDP1 were identified as epigenetic prognostic markers in LUAD and found out risk factors (P<0.05; HRs, 1.0012-1.0740). Whereas potential drug candidates for targeted therapy. ARRB1 and CBX7 were considered as protective factors (P<0.05; HRs, 0.9512 and 0.8885, respectively). In the present study, we firstly developed an epigenetic- The expression of 16 ERGs in LUAD and normal lung related prognostic signature based on TCGA dataset of samples were presented in Figure 3B, and the 497 LUAD patients, and then validated it in both correlation between these ERGs could be seen in Figure GSE31210 and GSE50081 datasets. More importantly, a 3C. Due to the important prognostic value of the new nomogram was created for predicting the overall candidate genes, their genetic alterations were analyzed. survival (OS) of LUAD patients based on five epigenetic- As shown in Figure 3D, missense mutation is the most related genes (ERGs). The accurate prediction function of common type of mutation, and there are 10 genes with the nomogram was evaluated. Moreover, we further mutation rate ≥3%, among which PRKDC mutation is screened out candidate targeted chemotherapy drugs to the most frequent (12%). the five ERGs. In conclusion, our study may provide new ideas for epigenetic-related prognostic biomarkers, Development of epigenetic-related signature thereby, highlighting the need to identify high risk patients and eventually delivering more effective targeted To eliminate highly correlated ERGs and prevent chemotherapeutic drugs for LUAD patients. overfitting of the signature, the Lasso regression analysis was performed (Figure 4A, 4B). Finally, five RESULTS ERGs were confirmed by multivariate Cox regression analysis and applied to develop an epigenetic-related Identifying differentially expressed ERGs prognostic signature (Table 1). The signature was established to assess the prognosis of each LUAD The flow diagram of our study is illustrated in Figure patient as follows: 1A. Firstly, we downloaded mRNA data of 497 LUAD samples and 54 corresponding normal lung samples and Risk score = (-0.03706×expression level of ARRB1) + corresponding clinical information from the TCGA (0.015474×expression level of PARP1) + (0.004509 database. Meanwhile, a total of 720 ERGs were obtained ×expression level of YWHAZ) + (0.001132×expression from the EpiFactors database. Then, we matched 720 level of TFDP1) + (0.004303×expression level of ERGs with LUAD-related mRNA data, 91 differentially PKM). expressed ERGs were identified (|log FC| > 1.0, adjusted P value < 0.05), including 12 downregulated and 79 According to above formula, the risk scores of 426 upregulated ERGs (Figure 1). LUAD patients were calculated, and patients were clustered into high and low risk groups by median risk GO and KEGG enrichment analyses score. The risk score (Figure 5A) and survival status (Figure 5B) of 426 LUAD patients are presented. As GO analysis results indicated that 91 ERGs were shown in Figure 5C, patients in the high risk group had mainly enriched in 422 Go terms, such as covalent significantly poorer OS compared to those in the low chromatin modification, histone modification, chromatin risk group. The prognostic signature exhibited good remodeling, peptidyl-lysine modification, regulation of predictive performance and accuracy for predicting the chromosome organization and so forth (Figure 2A, 2B). 1-, 3- and 5-year OS (Figure 5D). www.aging-us.com 18702 AGING Figure 1. Differentially expressed epigenetic-related genes(ERGs) in lung adenocarcinoma (LUAD). (A) A flow diagram of the study. (B) Heatmap of ERGs between LUAD and nontumor tissues in TCGA database. The color from green to orange represents the progression from low expression to high expression. (C) Volcano plot of ERGs in TCGA database. The orange dots in the plot represents upregulated genes and green dots represents downregulated genes with statistical significance. Gray dots represent no differentially expressed genes. www.aging-us.com 18703 AGING Relationships between risk score and bronchioloalveolar carcinoma, non-mucinous, and clinicopathological factors papillary adenocarcinoma (Figure 6B). Furthermore, the expression of the five crucial genes and Next, Univariate Cox analysis data demonstrated that clinicopathological factors in high and low risk groups pathologic stage, T stage, N stage and the risk score were are presented
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