Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (6): 26-34.doi: 10.6040/j.issn.1671-7554.0.2021.0110

Previous Articles     Next Articles

Value of abnormal methylation of cg16212145 on GZMB gene in early screening of gastric cancer

WANG Jing1,2, XIE Yan1,2, LI Peilong1,2, DU Lutao1,2, WANG Chuanxin1,2   

  1. 1. Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China;
    2. Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan 250033, Shandong, China
  • Published:2022-06-17

PDF (PC)

511

Abstract: Objective To obtain the specific genome-wide methylation profile of gastric cancer derived from peripheral blood mononuclear cells(PBMC), and to explore the clinical value of methylation points derived from PBMC in the early diagnosis of gastric cancer. Methods The genome-wide DNA methylation status of PBMC in 20 gastric cancer patients and 20 healthy controls was detected with Methylation850 BeadChip. The gastric cancer-specific methylation profile was constructed and differentially methylated points(DMPs)were obtained. Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis were performed on the genes where DMPs were located for functional prediction. Statistical screening of DMPs was performed using a random forest-based multi-factor filtering method. Next-generation sequencing-based multiplex target region methylation enrichment sequencing was performed on 34 patients with stage I gastric cancer and 21 healthy controls to verify the selected DMPs. Results The results of methylation BeadChip showed PBMC from gastric cancer patients had unique genome-wide methylation profile. A total of 5 883 DMPs were obtained with |Δβ|>0.06 and adjust P<0.05 as pre-screening conditions, including 2 513 hypermethylated sites and 3 370 hypomethylated sites. GO analysis and KEGG analysis showed that 2 677 genes where 5 883 DMPs were located were mainly associated with MAPK signaling pathway and transcriptional dysregulation in cancer. Granzyme B(GZMB)gene cg16212145 was hypermethylated in PBMC of gastric cancer patients, and the difference was statistically significant(Δβ=0.0807, adjust P=0.001). The results of multiple target region methylation enrichment sequencing showed that abnormal methylation status of CpG site cg16212145 could distinguish patients with stage I gastric cancer from healthy controls(AUC=0.807, P<0.001). Conclusion Gastric cancer patients have a specific genome-wide methylation profile derived from PBMC. The GZMB gene cg16212145 exhibits high methylation status in PBMC of gastric cancer patients, which has important clinical value in the early screening of gastric cancer.

Key words: Gastric cancer, DNA methylation, Peripheral blood mononuclear cell, Early screening, Markers

CLC Number: 

  • R735.2
[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries [J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] Sun W, Yan L. Gastric cancer: current and evolving treatment landscape [J]. Chin J Cancer, 2016, 35(1): 83. doi: 10.1186/s40880-016-0147-6.
[3] Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015 [J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[4] Van Cutsem E, Sagaert X, Topal B, et al. Gastric cancer [J]. Lancet, 2016, 388(10060): 2654-2664.
[5] Panarese I, De Vita F, Ronchi A, et al. Predictive biomarkers along gastric cancer pathogenetic pathways [J]. Expert Rev Anticancer Ther, 2017, 17(5): 417-425.
[6] Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: the current state and clinical perspectives [J]. Semin Cancer Biol, 2018, 51: 36-49. doi: 10.1016/j.semcancer.2017.12.004.
[7] Esteller M. Epigenetics in cancer [J]. N Engl J Med, 2008, 358(11): 1148-1159.
[8] Ren J, Lu P, Zhou X, et al. Genome-scale methylation analysis of circulating cell-Free DNA in gastric cancer patients [J]. Clin Chem, 2022, 68(2): 354-364.
[9] Tahara T, Arisawa T. DNA methylation as a molecular biomarker in gastric cancer [J]. Epigenomics, 2015, 7(3): 475-486.
[10] Zhang Y, Petropoulos S, Liu J, et al. The signature of liver cancer in immune cells DNA methylation [J]. Clin Epigenetics, 2018, 10: 8. doi: 10.1186/s13148-017-0436-1.
[11] Klumper N, Ralser DJ, Bawden EG, et al. LAG3(LAG-3, CD223)DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma [J]. J Immunother Cancer, 2020, 8(1): e000552. doi: 10.1136/jitc-2020-000552.
[12] Velotti F, Barchetta I, Cimini FA, et al. Granzyme B in inflammatory diseases: apoptosis, inflammation, extracellular matrix remodeling, epithelial-to-mesenchymal transition and fibrosis [J]. Front Immunol, 2020, 11: 587581. doi: 10.3389/fimmu.2020.587581.
[13] Turner CT, Lim D, Granville DJ. Granzyme B in skin inflammation and disease [J]. Matrix Biol, 2019, 75-76: 126-140. doi: 10.1016/j.matbio.2017.12.005.
[14] Jeong KH, Kim SK, Seo JK, et al. Association of GZMB polymorphisms and susceptibility to non-segmental vitiligo in a Korean population [J]. Sci Rep, 2021, 11(1): 397. doi: 10.1038/s41598-020-79705-0.
[15] Hiroyasu S, Zeglinski MR, Zhao H, et al. Granzyme B inhibition reduces disease severity in autoimmune blistering diseases [J]. Nat Commun, 2021, 12(1): 302. doi: 10.1038/s41467-020-20604-3.
[16] Zhang Z, Zhang Y, Xia S, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity [J]. Nature, 2020, 579(7799): 415-420.
[17] Yao K, Uedo N, Kamada T, et al. Guidelines for endoscopic diagnosis of early gastric cancer [J]. Dig Endosc, 2020, 32(5): 663-698.
[18] 管鑫, 李俊垚, 王明慧, 等. 胃镜在健康体检人群胃早癌及癌前疾病筛查中的临床意义[J]. 中国内镜杂志, 2019, 25(7): 34-41. GUAN Xin, LI Junyao, WANG Minghui, et al. Clinical significance of gastroscope in healthy population screening of early gastric cancer and precancerous diseases [J]. China Journal of Endoscopy, 2019, 25(7): 34-41.
[19] Luo D, Yang Q, Wang H, et al. A predictive model for assessing prognostic risks in gastric cancer patients using gene expression and methylation data [J]. BMC Med Genomics, 2021, 14(1): 14. doi: 10.1186/s12920-020-00856-0.
[20] Wen J, Zheng T, Hu K, et al. Promoter methylation of tumor-related genes as a potential biomarker using blood samples for gastric cancer detection [J]. Oncotarget, 2017, 8(44): 77783-77793.
[21] Skvortsova K, Stirzaker C, Taberlay P. The DNA methylation landscape in cancer [J]. Essays Biochem, 2019, 63(6): 797-811.
[22] Morrow JD, Cho MH, Hersh CP, et al. DNA methylation profiling in human lung tissue identifies genes associated with COPD [J]. Epigenetics, 2016, 11(10): 730-739.
[23] Pan Y, Liu G, Zhou F, et al. DNA methylation profiles in cancer diagnosis and therapeutics [J]. Clin Exp Med, 2018, 18(1): 1-14.
[24] Li T, Chen X, Gu M, et al. Identification of the subtypes of gastric cancer based on DNA methylation and the prediction of prognosis [J]. Clin Epigenetics, 2020, 12(1): 161. doi: 10.1186/s13148-020-00940-3.
[25] Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients [J]. Nat Rev Cancer, 2011, 11(6): 426-437.
[26] van der Pol Y, Mouliere F. Toward the early detection of cancer by decoding the epigenetic and environmental fingerprints of cell-free DNA [J]. Cancer Cell, 2019, 36(4): 350-368.
[27] Machlowska J, Baj J, Sitarz M, et al. Gastric Cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies [J]. Int J Mol Sci, 2020, 21(11): 4012. doi: 10.3390/ijms21114012.
[28] Lin C, He H, Liu H, et al. Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer [J]. Gut, 2019, 68(10): 1764-1773.
[29] Parashar S, Cheishvili D, Mahmood N, et al. DNA methylation signatures of breast cancer in peripheral T-cells [J]. BMC Cancer, 2018, 18(1): 574. doi: 10.1186/s12885-018-4482-7.
[30] 陈海燕. CA724、CEA、CA242、CA199肿瘤标志物联合检验在胃癌中的诊断价值[J]. 中国医药导报,2012, 9(31): 97-98. Chen HY. CA724、CEA、CA242、CA199 Diagnosis value of CA724, CEA, CA242, CA199 tumor markers for detecting gastric cancer [J]. Medicine Industry Information,2012, 9(31): 97-98.
[31] Konishi M, Erdem SS, Weissleder R, et al. Imaging Granzyme B activity assesses immune-mediated myocarditis [J]. Circ Res, 2015, 117(6): 502-512.
[32] Wu CH, Li J, Li L, et al. Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells [J]. J Extracell Vesicles, 2019, 8(1): 1588538. doi: 10.1080/20013078.2019.1588538.
[33] Wu Y, Wan X, Jia G, et al. Aberrantly methylated and expressed genes as prognostic epigenetic biomarkers for colon cancer [J]. DNA Cell Biol, 2020, 39(11): 1961-1969.
[1] WANG Ye, WANG Gang, NAN Haiou, CAI Yuling, LI Jiayu, WANG Haifeng, YAN Yingjie, JIANG Zhiwei. Correlation between perioperative heart rate variability and inflammatory indicators in gastric cancer patients [J]. Journal of Shandong University (Health Sciences), 2026, 64(4): 23-30.
[2] XUE Fuzhong. Theoretical and methodological framework for multimodal big data cohort design based on AI language representation [J]. Journal of Shandong University (Health Sciences), 2025, 63(8): 1-16.
[3] ZHU Yongcai, XIE Yan, QI Qiuchen, LI Peilong, WANG Chuanxin, DU Lutao. Value of a combined model based on ATM gene methylation of peripheral blood mononuclear cells in the early diagnosis of pancreatic cancer [J]. Journal of Shandong University (Health Sciences), 2025, 63(6): 78-88.
[4] JIA Ruoxi, LYU Li, LIU Hanyun, WU Yinping, LI Fengcai, ZHAO Zehua, WANG Kai, FAN Yuchen. Diagnostic value of blood cell count-related biomarkers in predicting 28-day mortality in acute-on-chronic hepatitis b liver failure [J]. Journal of Shandong University (Health Sciences), 2025, 63(6): 89-99.
[5] ZHAO Hanqing, ZHOU Xinrui, LI Zijian, TANG Xing. Application of circulating tumor cells combined with serological detection in non-small cell lung cancer [J]. Journal of Shandong University (Health Sciences), 2025, 63(5): 79-85.
[6] DU Xue, LI Chunxia, LIU Yunxia, ZHANG Tao. Dynamic prediction model for the colorectal cancer patients prognosis based on MFPC-Cox [J]. Journal of Shandong University (Health Sciences), 2025, 63(5): 101-110.
[7] 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.
[8] CHEN Wenliang, WANG Huanhuan, HAO Jinjin, GONG Rui, ZHAO Qiang, ZHANG Fei, GAO Lei, DONG Jingxun. The role of lncRNA PVT1 in prognostic assessment and malignant progression of gastric cancer: a study based on nomogram model and functional cellular experiments [J]. Journal of Shandong University (Health Sciences), 2025, 63(10): 61-71.
[9] WANG Jing, LIU Xiaofei, ZENG Rong, XU Changjuan, ZHANG Jintao, DONG Liang. Identification of necroptosis-related biomarkers in asthma based on machine learning algorithms [J]. Journal of Shandong University (Health Sciences), 2024, 62(7): 21-32.
[10] GUO Zhenjiang, WANG Ning, ZHAO Guangyuan, DU Liqiang, CUI Zhaobo, LIU Fangzhen. Development of preoperative models for predicting positive esophageal margin in proximal gastric cancer based on machine learning [J]. Journal of Shandong University (Health Sciences), 2024, 62(7): 78-83.
[11] SHI Shuochuan, ZENG Rong, ZHANG Jintao, ZHANG Dong, PAN Yun, LIU Xiaofei, XU Changjuan, WANG Ying, DONG Liang. Bioinformatics-based exploration of potential differential immune genes and immune infiltration signatures in bronchial asthma [J]. Journal of Shandong University (Health Sciences), 2024, 62(5): 43-53.
[12] BAI Xiaoliang, SUN Panpan, WANG Hongli, GONG Shunzhi, SUN Yunqi, SHU Meng, QI Xiaoliang. Animal experiment of medical thoracoscopic splanchnotomy [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 9-13.
[13] GUO Xin, MENG Jun, ZHENG Shiliang, DONG Xiuhong. Correlation between frailty and body composition in elderly patients with gastric cancer [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 40-47.
[14] GUO Haonan, ZHOU Peng, LI Xiaolei, YUE Tao, XU Jing, SHAO Changxiu, HE Qingqing, ZHUANG Dayong. Efficacy of total parathyroidectomy and total parathyroidectomy with autotransplantation in treatment of secondary hyperparathyroidism [J]. Journal of Shandong University (Health Sciences), 2024, 62(12): 72-81.
[15] WANG Yutao, SUN Yan. Comprehensive analysis of single-cell transcriptomics and machine learning reveals potential biomarkers for abdominal aortic aneurysm [J]. Journal of Shandong University (Health Sciences), 2024, 62(11): 40-53.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd