肾透明细胞癌中预后相关RNA编辑位点的筛选

doi:10.6040/j.issn.1671-7554.0.2023.0150

摘要/Abstract

摘要： 目的探讨肾透明细胞癌(ccRCC)中与患者生存预后相关的RNA编辑位点。方法下载癌症基因组图谱(TCGA)中RNA编辑位点的表达数据,使用最小绝对收缩和选择算子(LASSO)及Cox回归筛选出与ccRCC预后密切关联的RNA编辑位点。根据多因素Cox结果计算患者的风险评分后构建预后模型和列线图,进一步采用接受者操作特征(ROC)曲线评估预后模型和列线图的准确性,并进行相关的功能学分析。结果共筛选出25个与ccRCC预后相关的RNA编辑位点。根据风险评分的中位值将患者分为高风险组(n=222)与低风险组(n=226)。Kaplan-Meier生存分析结果显示,高风险组患者的总生存时间与疾病无进展生存时间均低于低风险组(P<0.001)。预后模型和列线图预测患者1、3、5年生存的曲线下面积(AUC)值分别为0.801、0.824和0.806、0.858,0.833和0.821。风险分组之间具备不同的生物学功能及药物敏感性。结论通过公共数据库筛选出的25个RNA编辑位点有望会成为ccRCC患者新的预后标记物。

关键词: 肾透明细胞癌, RNA编辑, 预后模型, 免疫治疗

Abstract: Objective To explore RNA editing sites associated with survival and prognosis in clear cell renal cell carcinoma(ccRCC). Methods After the expression data of RNA editing sites in the Cancer Genome Atlas(TCGA)were downloaded, the minimum absolute contraction, selection operator(LASSO)and Cox regression were used to identify RNA editing sites closely associated with ccRCC prognosis. A prognostic model and nomogram were constructed after the risk scores were calculated based on the multivariate Cox results. The accuracy of the prognostic model and nomogram was evaluated with the receiver operating characteristic(ROC)curve, and the relevant functional analysis was performed. Results A total of 25 RNA editing sites associated with ccRCC prognosis were screened. Patients were divided into the high-risk group(n=222)and low-risk group(n=226)based on the median risk score. Kaplan-Meier survival analysis showed that the overall survival(OS)and progression-free survival(PFS)were in shorter in the high-risk group than in the low-risk group(P<0.001). The area under the ROC curve(AUC)of 1-year, 3-year and 5-year survival predicted by the prognosis model were 0.801, 0.824 and 0.806, and those predicted by the nomogram were 0.858, 0.833 and 0.821, respectively. There were differences in biological function and drug sensitivity between the two groups. Conclusion The 25 RNA editing sites are expected to become new prognostic markers and drug therapeutic targets for patients with ccRCC.

Key words: Renal clear cell carcinoma, RNA editing, Prognostic model, Immunotherapy

中图分类号:

R692

宋兆录,董正璇,彭传真,黄彩娜,胡克清,黄永胜,阎磊. 肾透明细胞癌中预后相关RNA编辑位点的筛选[J]. 山东大学学报 (医学版), 2023, 61(9): 69-78.

SONG Zhaolu, DONG Zhengxuan, PENG Chuanzhen, HUANG Caina, HU Keqing, HUANG Yongsheng, YAN Lei. Screening of prognosis-related RNA editing sites in clear cell renal cell carcinoma[J]. Journal of Shandong University (Health Sciences), 2023, 61(9): 69-78.

参考文献

[1] Linehan WM, Schmidt LS, Crooks DR, et al. The metabolic basis of kidney Cancer [J]. Cancer Discov, 2019, 9(8): 1006-1021.
[2] 中国医疗保健国际交流促进会泌尿健康促进分会. 肾癌基因检测中国专家共识(2021版)[J]. 现代泌尿外科杂志, 2022, 27(3): 192-200. China Association for the Promotion of International Exchange of Medical Care Urinary Health Promotion Branch. Chinese expert consensus on kidney cancer gene testing(2021 version)[J]. Journal of Modern Urology, 2022, 27(3): 192-200.
[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020 [J]. CA Cancer J Clin, 2020, 70(1): 7-30.
[4] Go H, Kang MJ, Kim PJ, et al. Development of response classifier for vascular endothelial growth factor receptor(VEGFR)-tyrosine kinase inhibitor(TKI)in metastatic renal cell carcinoma [J]. Pathol Oncol Res, 2019, 25(1): 51-58.
[5] Liu J, Wang F, Zhang Y, et al. ADAR1-Mediated RNA editing and its role in cancer [J]. Front Cell Dev Biol, 2022, 10: 956649. doi: 10.3389/fcell.2022.956649.
[6] Kurkowiak M, Arcimowicz L, Chrusciel E, et al. The effects of RNA editing in cancer tissue at different stages in carcinogenesis [J]. RNA Biol, 2021, 18(11): 1524-1539.
[7] Park E, Jiang Y, Hao L, et al. Genetic variation and microRNA targeting of A-to-I RNA editing fine tune human tissue transcriptomes [J]. Genome Biol, 2021, 22(1): 77. doi: 10.1186/s13059-021-02287-1.
[8] Peng X, Xu X, Wang Y, et al. A-to-I RNA editing contributes to proteomic diversity in cancer [J]. Cancer Cell, 2018, 33(5): 817-828.
[9] Chigaev M, Yu H, Samuels DC, et al. Genomic positional dissection of RNA editomes in tumor and normal samples [J]. Front Genet, 2019, 10: 211. doi: 10.3389/fgene.2019.00211. eCollection 2019.
[10] Sun Z, Qin X, Fang J, et al. Multi-omics analysis of the expression and prognosis for FKBP gene family in renal cancer [J]. Front Oncol, 2021, 11: 697534. doi: 10.3389/fonc.2021.697534. eCollection 2021.
[11] Teng PC, Liang Y, Yarmishyn AA, et al. RNA Modifications and epigenetics in modulation of lung cancer and pulmonary diseases [J]. Int J Mol Sci, 2021, 22(19):10592. doi: 10.3390/ijms221910592.
[12] Song B, Shiromoto Y, Minakuchi M, et al. The role of RNA editing enzyme ADAR1 in human disease [J]. Wiley Interdiscip Rev RNA, 2022, 13(1): e1665. doi: 10.1002/wrna.1665.
[13] Jiang L, Hao Y, Shao C, et al. ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance [J]. Clin Invest, 2022, 132(6): e143397. doi: 10.1172/JCI143397.
[14] Nakamura K, Shigeyasu K, Okamoto K, et al. ADAR1 and AZIN1 RNA editing function as an oncogene and contributes to immortalization in endometrial cancer [J]. Gynecologic Oncology, 2022, 166(2): 326-333.
[15] Shen P, Yang T, Chen Q, et al. CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-I RNA-editing [J]. Mol Cancer, 2021, 20(1): 51. doi: 10.1186/s12943-021-01333-7.
[16] Martinez HD, Jasavala RJ, Hinkson I, et al. RNA editing of androgen receptor gene transcripts in prostate cancer cells [J]. J Biol Chem, 2008, 283(44): 29938-29949.
[17] Shigeyasu K, Okugawa Y, Toden S, et al. AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer [J]. JCI Insight, 2018, 3(12): e99976. doi: 10.1172/jci.insight.99976.
[18] Okugawa Y, Toiyama Y, Shigeyasu K, et al. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer [J]. Transl Med, 2018, 16(1): 366. doi: 10.1186/s12967-018-1740-z.
[19] Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy [J]. Cell, 2017, 168(4): 707-723.
[20] 胡立勇,钟浩,房娟娟,等. 基于数据库分析CCR基因对肾透明细胞癌预后的预测价值[J]. 山东大学学报(医学版), 2023, 61(4): 49-55. HU Liyong, ZHONG Hao, FANG Juanjuan, et al. Prognostic value of CCR gene in clear cell renal cell carcinoma based on database [J]. Journal of Shandong University(Health Sciences), 2023, 61(4): 49-55.
[21] Tang SJ, Shen H, An O, et al. Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development [J]. Nat Commun, 2020, 11(1): 799.
[22] 杨朝华, 田宇, 安治国. RNA编辑与肿瘤[J]. 中国实验诊断学, 2004, 8(1): 89-91. YANG Zhaohua, TIAN Yu, AN Zhiguo. RNA editing and tumor [J]. Chinese Journal of Laboratory Diagnosis, 2004, 8(1): 89-91.
[23] Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation [J]. Genes Dev, 2015, 29(13): 1343-1355.
[24] Chen L, Li Y, Lin CH, et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma [J]. Nat Med, 2013, 19(2): 209-216.
[25] Xu LD, Öhman M. ADAR1 Editing and its role in cancer [J]. Genes(Basel), 2018, 10(1):12. doi: 10.3390/genes10010012.
[26] Wu YM, Guo Y, Yu H, et al. RNA editing affects cis-regulatory elements and predicts adverse cancer survival [J]. Cancer Med, 2021, 10(17): 6114-6127.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed