GPR133基因甲基化在早期胃癌淋巴结转移预测中的作用

doi:10.6040/j.issn.1671-7554.0.2024.0670

摘要/Abstract

摘要： 目的通过定量检测GPR133基因甲基化位点,探讨其在早期胃癌淋巴结转移(lymph node metastasis, LNM)预测中的临床价值。方法回顾性选取2023年1月至2024年5月山东大学第二医院消化内科收治的100例T1期胃癌患者为研究对象;采用MethylationEPIC芯片分析T1期胃癌LNM阳性和阴性患者的手术组织样本,评估全基因组甲基化状态并识别差异甲基化位点(differentially methylated positions, DMPs);基于基因富集和功能预测确定候选DMPs;选用20例LNM阳性及80例阴性患者的福尔马林固定石蜡包埋(formalin-fixed and parrfin-embedded, FFPE)切片通过焦磷酸测序验证候选DMPs的甲基化水平;采用受试者操作特征曲线下面积(area under curve, AUC)评估DMPs在早期胃癌LNM诊断中的临床价值。结果 MethylationEPIC芯片分析显示,T1期胃癌LNM阳性样本具有特异性甲基化图谱;以|Δβ|≥0.1且P<0.01为筛选标准,共初步筛选出1 794个DMPs;根据基因匹配、TCGA数据库分析及cAMP binding途径的富集结果,明确GPR133基因上的cg00633768为候选位点;焦磷酸测序结果显示,cg00633768位点甲基化水平能够显著区分LNM阳性和阴性样本(AUC=0.869,敏感性64.3%,特异性100%,截断值0.618 9)。结论与LNM阴性患者相比,GPR133基因的cg00633768位点在LNM阳性患者中呈显著高甲基化状态,对预测早期胃癌LNM具有重要的临床价值。

关键词: 早期胃癌, 淋巴结转移, 甲基化, G蛋白偶联受体, GPR133

Abstract: Objective To explore the clinical value of quantitatively detecting methylation sites in the GPR133 gene for predicting lymph node metastasis(LNM)in early gastric cancer. Methods This retrospective study included 100 patients with T1 stage gastric cancer treated at the Department of Gastroenterology, Second Hospital of Shandong University, from January 2023 to May 2024. The MethylationEPIC array was used to analyze the whole-genome methylation status of surgical tissue samples from LNM-positive and LNM-negative patients, so as to identify differentially methylated positions(DMPs). Candidate DMPs were determined based on gene enrichment analysis and functional prediction. Pyrosequencing was performed on FFPE sections from 20 LNM-positive and 80 LNM-negative patients to validate the methylation levels of candidate DMPs. The clinical value of DMPs in diagnosing early gastric cancer lymph node metastasis was assessed using the area under the receiver operating characteristic curve(AUC). Results MethylationEPIC array analysis revealed a specific methylation pattern in T1 stage gastric cancer LNM-positive samples. Using a threshold of |Δβ|≥0.1 and P<0.01, a total of 1,794 DMPs were initially identified. According to the results of gene matching and TCGA database analysis and cAMP binding pathway enrichment, cg00633768 on GPR133 gene was identified as a candidate site. Pyrosequencing results showed that cg00633768 methylation level could significantly distinguish between LNMS positive and negative samples(AUC=0.869, sensitivity=64.3%, specificity=100%, cut-off value=0.618 9). Conclusion The methylation level of cg00633768 in the GPR133 gene is significantly higher in LNM-positive patients compared to LNM-negative patients. This site has substantial clinical value for predicting lymph node metastasis in early gastric cancer.

Key words: Early gastric cancer, Lymph node metastasis, Methylation, G-protein coupled receptor, GPR133

中图分类号:

R735.2

张洁,赵颖慧,董雅琪,李娟,李培龙,杜鲁涛. GPR133基因甲基化在早期胃癌淋巴结转移预测中的作用[J]. 山东大学学报 (医学版), 2025, 63(3): 76-84.

ZHANG Jie, ZHAO Yinghui, DONG Yaqi, LI Juan, LI Peilong, DU Lutao. Role of GPR133 gene methylation in predicting lymph node metastasis in early gastric cancer[J]. Journal of Shandong University (Health Sciences), 2025, 63(3): 76-84.

参考文献

[1] Thrift AP, Wenker TN, El-Serag HB. Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention[J]. Nat Rev Clin Oncol, 2023, 20(5): 338-349.
[2] Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: an overview[J]. Int J Cancer, 2021. doi:10.1002/ijc.33588
[3] 陈平, 徐莹, 吴云林. 消化内镜在早期胃癌诊断中的应用进展[J]. 诊断学理论与实践, 2022, 21(5): 551-554. CHEN Ping, XU Ying, WU Yunlin. Application of digestive endoscopy in the diagnosis of early gastric cancer[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(5): 551-554.
[4] Ping YQ, Xiao P, Yang F, et al. Structural basis for the tethered peptide activation of adhesion GPCRs[J]. Nature, 2022, 604(7907): 763-770.
[5] Yang DH, Zhou QT, Labroska V, et al. G protein-coupled receptors: structure- and function-based drug discovery[J]. Signal Transduct Target Ther, 2021, 6(1): 7. doi:10.1038/s41392-020-00435-w
[6] Liebscher I, Cevhero glu O, Hsiao CC, et al. A guide to adhesion GPCR research[J]. FEBS J, 2022, 289(24): 7610-7630.
[7] Stephan G, Frenster JD, Liebscher I, et al. Activation of the adhesion G protein-coupled receptor GPR133 by antibodies targeting its N-terminus[J]. J Biol Chem, 2022, 298(6): 101949. doi:10.1016/j.jbc.2022.101949
[8] Araújo D, Ribeiro E, Amorim I, et al. Repurposed drugs in gastric cancer[J]. Molecules, 2022, 28(1): 319. doi:10.3390/molecules28010319
[9] Lee KG, Shin CI, Kim SG, et al. Can endoscopic ultrasonography(EUS)improve the accuracy of clinical T staging by computed tomography(CT)for gastric cancer?[J]. Eur J Surg Oncol, 2021, 47(8): 1969-1975.
[10] Stephan G, Haddock S, Wang S, et al. Modulation of GPR133(ADGRD1)signaling by its intracellular interaction partner extended synaptotagmin 1[J]. Cell Rep, 2024, 43(5): 114229. doi:10.1016/j.celrep.2024.114229
[11] Noh CK, Jung MW, Shin SJ, et al. Analysis of endoscopic features for histologic discrepancies between biopsy and endoscopic submucosal dissection in gastric neoplasms: 10-year results[J]. Dig Liver Dis, 2019, 51(1): 79-85.
[12] 徐惠绵,王鑫. 我国胃癌诊治临床研究现状与展望[J]. 中华胃肠外科杂志, 2020, 23(2): 109-114. XU Huimian, WANG Xin. Current status and prospects of clinical research on diagnosis and treatment of gastric cancer in China[J]. Chinese Journal of Gastrointestinal Surgery, 2020, 23(2): 109-114.
[13] Zhang YF, Shi FZ, Fan YX, et al. Comparison of prognostic outcomes between endoscopic submucosal dissection and surgical treatment for early gastric cancer: a retrospective cohort study[J]. BMC Gastroenterol, 2024, 24(1): 98. doi:10.1186/s12876-024-03186-y
[14] Association JGC. Japanese gastric cancer treatment guidelines 2021(6th edition)[J]. Gastric Cancer, 2023, 26(1): 1-25.
[15] Ono H, Yao KS, Fujishiro M, et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer(second edition)[J]. Dig Endosc, 2021, 33(1): 4-20.
[16] 赫捷, 陈万青, 李兆申, 等. 中国胃癌筛查与早诊早治指南(2022,北京)[J]. 中华肿瘤杂志, 2022, 31(7): 643-666. HE Jie, CHEN Wanqing, LI Zhaoshen, et al. China guideline for the screening, early detection and early treatment of gastric cancer(2022, Beijing)[J]. Chines Journal of Onclolgy, 2022, 44(7): 634-666.
[17] 杜婉莹, 徐洪雨. 内镜黏膜下剥离术治疗早期胃癌的研究进展[J]. 国际消化病杂志, 2019, 39(4): 247-251. DU Wanying, XU Hongyu. Advances in endoscopic submucosal dissection for early gastric cancer[J]. International Journal of Digestive Diseases, 2019, 39(4): 247-251.
[18] Lissa D, Robles AI. Methylation analyses in liquid biopsy[J]. Transl Lung Cancer Res, 2016, 5(5): 492-504.
[19] Luo HY, Wei W, Ye ZY, et al. Liquid biopsy of methylation biomarkers in cell-free DNA[J]. Trends Mol Med, 2021, 27(5): 482-500.
[20] Marrugo-Ramírez J, Mir M, Samitier J. Blood-based cancer biomarkers in liquid biopsy: a promising non-invasive alternative to tissue biopsy[J]. Int J Mol Sci, 2018, 19(10): 2877. doi:10.3390/ijms19102877
[21] Tseng CC, Liao WT, Wong MC, et al. Cell lineage-specific methylome and genome alterations in gout[J]. Aging, 2021, 13(3): 3843-3865.
[22] Iqbal MA, Li MY, Lin J, et al. Preliminary study on the sequencing of whole genomic methylation and transcriptome-related genes in thyroid carcinoma[J]. Cancers, 2022, 14(5): 1163. doi:10.3390/cancers14051163
[23] Hassani B, Attar Z, Firouzabadi N. The renin-angiotensin-aldosterone system(RAAS)signaling pathways and cancer: foes versus allies[J]. Cancer Cell Int, 2023, 23(1): 254. doi:10.1186/s12935-023-03080-9
[24] Luo JQ, Yu FX. GPCR-hippo signaling in cancer[J]. Cells, 2019, 8(5): 426. doi:10.3390/cells8050426
[25] Bayin NS, Frenster JD, Kane JR, et al. GPR133(ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth[J]. Oncogenesis, 2016, 5(10): e263. doi:10.1038/oncsis.2016.63
[26] Monk KR, Hamann J, Langenhan T, et al. Adhesion G protein-coupled receptors: from in vitro pharmacology to in vivo mechanisms[J]. Mol Pharmacol, 2015, 88(3): 617-623.

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