血清和尿液Hugl-2基因甲基化检测对肾细胞癌的诊断价值-东南大学学报医学版

血清和尿液Hugl-2基因甲基化检测对肾细胞癌的诊断价值

单位：1. 临汾市中心医院检验科, 山西临汾 041000;
2. 临汾市中心医院肿瘤科, 山西临汾 041000

分类号：R737.11

出版年·卷·期（页码）：2022·41·第三期（325-331）

摘要：

目的：研究血清和尿液中Hugl-2基因甲基化水平对肾细胞癌（RCC）的诊断价值。方法：利用生物信息学分析工具分析RCC肿瘤组织及相匹配的正常组织中Hugl-2 mRNA表达及甲基化水平，并分析其与患者生存预后的关系。收集2018年5月至2021年3月在本院泌尿外科接受根治性肾切除术的148例RCC患者（RCC组）的肿瘤组织、相匹配的非癌肾实质组织、血清和尿液样本，另收集150例年龄、性别相匹配的非癌对照组人群，通过甲基化特异性PCR法检测Hugl-2基因甲基化情况。结果：基于生物信息学分析，TCGA数据库资料分析结果表明，Hugl-2 mRNA和蛋白在RCC组织中的表达低于正常组织（P<0.05），同时Hugl-2基因甲基化水平高于正常组织（P<0.05）；基于LinkedOmics网络工具，Hugl-2基因甲基化水平高与RCC患者的总体生存预后不良有关（Log-rank P<0.001）。在临床样本分析中，RCC组织标本中Hugl-2基因甲基化水平高于相配对的癌旁非癌肾实质组织样本（P<0.05），且RCC组患者血清和尿液样本中Hugl-2基因甲基化水平亦高于非癌对照组人群（P<0.05）。经Spearman相关系数分析，RCC组患者血清和尿液样本中Hugl-2基因甲基化水平均与肿瘤组织样本中Hugl-2基因甲基化水平呈正相关（r_s分别为0.352、0.486，均P<0.001）；且Hugl-2基因甲基化水平升高与TNM分期Ⅲ~Ⅳ期有关（P<0.05）。经受试者工作特征（ROC）曲线分析发现，检测血清和尿液样本中Hugl-2基因甲基化水平诊断RCC的曲线下面积（AUC）分别为0.818（95%CI：0.770~0.867）和0.958（95%CI：0.935~0.980），且尿液样本的AUC大于血清样本（P<0.001）。结论：检测血清或尿液样本中Hugl-2基因甲基化水平有望成为RCC的诊断手段，且尿液中Hugl-2基因甲基化水平对于RCC的诊断效能更高。

Objective: To investigate the diagnostic value of serum and urinary Hugl-2 gene methylation in renal cell carcinoma(RCC). Methods: Hugl-2 mRNA and protein expression and gene methylation were analyzed using bioinformatics analysis tool, and its correlation with the prognosis was also evaluated. The tumor tissue, matched non-cancerous renal parenchyma, serum and urine samples from 148 patients with RCC who underwent radical nephrectomy from May 2018 to March 2021 in our urological department were collected, while age and sex matched 150 non-cancer patients matched by age and sex ere also enrolled. The methylation of Hugl-2 gene in tissues, serum and urine was detected by methylation-specific PCR. Results: Based on bioinformatics analysis, data from the TCGA database showed that the expression of Hugl-2 mRNA and protein in RCC tissues was lower than that in normal tissues(P<0.05), while the methylation level of Hugl-2 gene was higher than that of normal tissue(P<0.05). High methylation levels of Hugl-2 were associated with poor overall survival in RCC patients, based on a network of tools known as LinkedOmics(Log-rank P<0.001). In the analysis of clinical samples, the methylation level of Hugl-2 gene in RCC tissue samples was higher than that in matched adjacent non-cancerous renal parenchyma tissue samples(P<0.05). In addition, the level of Hugl-2 gene methylation in serum and urine of patients with RCC was higher than that of non-cancer control group(P<0.05). The methylation level of Hugl-2 gene was positively correlated with the methylation level of Hugl-2 gene in serum and urine of patients with RCC by Spearman correlation coefficient analysis(r_s=0.352, 0.486, P<0.001). Hypermethylation of Hugl-2 gene was associated with TNM Ⅲ-Ⅳ stage(P<0.05). The area under ROC curve(AUC) of detecting Hugl-2 gene methylation in serum and urine was 0.818(95%CI:0.770-0.867) and 0.958(95%CI:0.935-0.980), respectively, and the AUC of urine was higher than that of serum(P<0.001). Conclusion: The methylation level of Hugl-2 gene in serum or urine samples is expected to be an diagnostic method for RCC, especially the methylation level of Hugl-2 gene in urine is more effective.

参考文献：

[1] ESCUDIER B,PORTA C,SCHMIDINGER M,et al.ESMO Guidelines Committee.Electronic address:clinicalguidelines@esmo.org.Renal cell carcinoma:ESMO Clinical Practice Guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2019,30(5):706-720.
[2] GRAY R E,HARRIS G T.Renal cell carcinoma:diagnosis and management[J].Am Fam Physician,2019,99(3):179-184.
[3] 李显,丁杰,岑祥莹,等.组蛋白赖氨酸特异性去甲基化酶1相互作用蛋白的研究进展[J].现代医学,2020,48(9):1224-1229.
[4] EVELONN E A,DEGERMAN S,KOHN L,et al.DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma(ccRCC)[J].Tumour Biol,2016,37(8):10219-10228.
[5] 李川川.肝癌组织hugl-1异常剪接体的功能的研究[D].济南:山东大学,2012.
[6] NAM K H,KIM M A,CHOE G,et al.Deregulation of the cell polarity protein lethal giant larvae 2(Lgl2) correlates with gastric cancer progression[J].Gastric Cancer,2014,17(4):610-620.
[7] MIAO Y,CAO F,LI P,et al.DNA methylation of Hugl-2 is a prognostic biomarker in kidney renal clear cell carcinoma[J].Clin Exp Pharmacol Physiol,2020,48(1):44-53.
[8] YANG K,WANG L,LE J,et al.Cell polarity:regulators and mechanisms in plants[J].J Integr Plant Biol,2020,62(1):132-147.
[9] CALLEJA M,MORATA G,CASANOVA J.Tumorigenic properties of drosophila epithelial cells mutant for lethal giant larvae[J].Dev Dyn,2016,245(8):834-843.
[10] DANIEL S G,RUSS A D,GUTHRIDGE K M,et al.miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila[J].Biol Open,2018,7(1):bio027391.
[11] 尚维伟,王亮,陈信浩.结直肠癌组织TRIM58表达、基因甲基化状态及临床意义[J].现代医学,2020,48(8):948-954.
[12] SKVORTSOVA K,STIRZAKER C,TABERLAY P.The DNA methylation landscape in cancer[J].Essays Biochem,2019,63(6):797-811.
[13] NUZZO P V,BERCHUCK J E,KORTHAUER K,et al.Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes[J].Nat Med,2020,26(7):1041-1043.
[14] 张慧娟,郑闪,冯晓莉.成人乳头状结构的肾细胞癌的诊断及鉴别诊断[J].诊断病理学杂志,2020,27(12):904-908,912.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录