MIR124-3 and NKX6-1 hypermethylation profiles accurately predict metachronous gastric lesions in a Caucasian population.
Epigenetics
Gastric cancer
MicroRNAs
Molecular markers
Precision medicine
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
21 Aug 2024
21 Aug 2024
Historique:
received:
11
06
2024
accepted:
23
07
2024
medline:
22
8
2024
pubmed:
22
8
2024
entrez:
21
8
2024
Statut:
epublish
Résumé
Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients. This case-cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan-Meier and Cox proportional hazards model analyses. MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03-5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07-8.95, p = 0.037). This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care.
Sections du résumé
BACKGROUND
BACKGROUND
Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients.
METHODS
METHODS
This case-cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan-Meier and Cox proportional hazards model analyses.
RESULTS
RESULTS
MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03-5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07-8.95, p = 0.037).
CONCLUSIONS
CONCLUSIONS
This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care.
Identifiants
pubmed: 39169394
doi: 10.1186/s13148-024-01712-z
pii: 10.1186/s13148-024-01712-z
doi:
Substances chimiques
MicroRNAs
0
Homeodomain Proteins
0
NKX6-1 protein, human
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113Subventions
Organisme : Fundação para a Ciência e a Tecnologia
ID : UI/BD/151488/2021
Organisme : HORIZON EUROPE Health
ID : 101095359
Organisme : UK Research and Innovation
ID : 10058099
Informations de copyright
© 2024. The Author(s).
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
pubmed: 33538338
doi: 10.3322/caac.21660
Park E, Nishimura M, Simoes P. Endoscopic advances in the management of gastric cancer and premalignant gastric conditions. World J Gastrointest Endosc. 2023;15(3):114–21.
pubmed: 37034969
pmcid: 10080555
doi: 10.4253/wjge.v15.i3.114
Libânio D, Braga V, Ferraz S, Castro R, Lage J, Pita I, et al. Prospective comparative study of endoscopic submucosal dissection and gastrectomy for early neoplastic lesions including patients’ perspectives. Endoscopy. 2019;51(1):30–9.
pubmed: 29969807
doi: 10.1055/a-0628-6601
Pimentel-Nunes P, Libânio D, Marcos-Pinto R, Areia M, Leja M, Esposito G, et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019. Endoscopy. 2019;51(4):365–88.
pubmed: 30841008
doi: 10.1055/a-0859-1883
Abe S, Oda I, Suzuki H, Nonaka S, Yoshinaga S, Nakajima T, et al. Long-term surveillance and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection. Endoscopy. 2015;47(12):1113–8.
pubmed: 26165734
doi: 10.1055/s-0034-1392484
Salvatori S, Marafini I, Laudisi F, Monteleone G, Stolfi C. Helicobacter pylori and gastric cancer: pathogenetic mechanisms. Int J Mol Sci. 2023;24(3):2895.
pubmed: 36769214
pmcid: 9917787
doi: 10.3390/ijms24032895
Jung DH, Kim JH, Chung HS, Park JC, Shin SK, Lee SK, et al. Helicobacter pylori eradication on the prevention of metachronous lesions after endoscopic resection of gastric neoplasm: a meta-analysis. PLoS ONE. 2015;10(4):e0124725.
pubmed: 25915048
pmcid: 4411104
doi: 10.1371/journal.pone.0124725
Ortigão R, Figueirôa G, Frazzoni L, Pimentel-Nunes P, Hassan C, Dinis-Ribeiro M, et al. Risk factors for gastric metachronous lesions after endoscopic or surgical resection: a systematic review and meta-analysis. Endoscopy. 2022;54(9):892–901.
pubmed: 35104897
doi: 10.1055/a-1724-7378
Cunha Neves JA, Rodriguez de Santiago E, Pohl H, Lorenzo-Zúñiga V, Cunha MF, Voiosu AM, et al. Perspectives and awareness of endoscopy healthcare professionals on sustainable practices in gastrointestinal endoscopy: results of the LEAFGREEN survey. Endoscopy. 2024;56:355–63.
pubmed: 38278158
doi: 10.1055/a-2240-9414
Zeng Y, Rong H, Xu J, Cao R, Li S, Gao Y, et al. DNA methylation: an important biomarker and therapeutic target for gastric cancer. Front Genet. 2022;13:823905.
pubmed: 35309131
pmcid: 8931997
doi: 10.3389/fgene.2022.823905
Kubota Y, Tanabe S, Azuma M, Horio K, Fujiyama Y, Soeno T, et al. Predictive significance of promoter DNA methylation of Cysteine Dioxygenase Type 1 (CDO1) in metachronous gastric cancer. J Gastric Cancer. 2021;21(4):379–91.
pubmed: 35079440
pmcid: 8753284
doi: 10.5230/jgc.2021.21.e35
Shin CM, Kim N, Yoon H, Choi YJ, Park JH, Park YS, et al. Aberrant DNA methylation maker for predicting metachronous recurrence after endoscopic resection of gastric neoplasms. Cancer Res Treat. 2022;54(4):1157–66.
pubmed: 35038821
pmcid: 9582476
doi: 10.4143/crt.2021.997
Suzuki R, Yamamoto E, Nojima M, Maruyama R, Yamano HO, Yoshikawa K, et al. Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk. J Gastroenterol. 2014;49(7):1135–44.
pubmed: 23942619
doi: 10.1007/s00535-013-0861-7
Asada K, Nakajima T, Shimazu T, Yamamichi N, Maekita T, Yokoi C, et al. Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study. Gut. 2015;64(3):388–96.
pubmed: 25379950
doi: 10.1136/gutjnl-2014-307094
Maeda M, Nakajima T, Oda I, Shimazu T, Yamamichi N, Maekita T, et al. High impact of methylation accumulation on metachronous gastric cancer: 5-year follow-up of a multicentre prospective cohort study. Gut. 2017;66(9):1721–3.
pubmed: 28003322
doi: 10.1136/gutjnl-2016-313387
Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut. 2015;64(11):1721–31.
pubmed: 25385008
doi: 10.1136/gutjnl-2014-308252
Kader F, Ghai M. DNA methylation-based variation between human populations. Mol Genet Genomics. 2017;292(1):5–35.
pubmed: 27815639
doi: 10.1007/s00438-016-1264-2
Elliott HR, Burrows K, Min JL, Tillin T, Mason D, Wright J, et al. Characterisation of ethnic differences in DNA methylation between UK-resident South Asians and Europeans. Clin Epigenetics. 2022;14(1):130.
pubmed: 36243740
pmcid: 9571473
doi: 10.1186/s13148-022-01351-2
Heerink JS, Oudega R, Hopstaken R, Koffijberg H, Kusters R. Clinical decision rules in primary care: necessary investments for sustainable healthcare. Prim Health Care Res Dev. 2023;24: e34.
pubmed: 37129072
pmcid: 10156469
doi: 10.1017/S146342362300021X
Rei A, Ortigão R, Pais M, Afonso LP, Pimentel-Nunes P, Dinis-Ribeiro M, et al. Metachronous lesions after gastric endoscopic submucosal dissection: first assessment of the FAMISH prediction score. Endoscopy. 2023;55(10):909–17.
pubmed: 37160262
doi: 10.1055/a-2089-6849
Lobo J, Constâncio V, Guimarães-Teixeira C, Leite-Silva P, Miranda-Gonçalves V, Sequeira JP, et al. Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors. Mol Oncol. 2021;15(4):846–65.
pubmed: 33513287
pmcid: 8024740
doi: 10.1002/1878-0261.12909
Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287–97.
pubmed: 24645800
doi: 10.1056/NEJMoa1311194
Macedo-Silva C, Constâncio V, Miranda-Gonçalves V, Leite-Silva P, Salta S, Lobo J, et al. DNA methylation biomarkers accurately detect esophageal cancer prior and post neoadjuvant chemoradiation. Cancer Med. 2023;12(7):8777–88.
pubmed: 36670548
pmcid: 10134363
doi: 10.1002/cam4.5623
Therneau T, Grambsch P. Modeling survival data: Extending the Cox model. 2000.
Therneau T. A package for survival analysis in R. 2023.
Harrison E, Drake T, Pius R. Quickly create elegant regression results tables and plots when modelling. R package version 1.0.8. 2024. https://github.com/ewenharrison/finalfit .
Niu Z, Liang D, Guan C, Zheng Y, Meng C, Sun X, et al. External validation of the FAMISH predicting score for early gastric cancer with endoscopic submucosal dissection. Eur J Gastroenterol Hepatol. 2024;36(1):26–32.
pubmed: 37642661
doi: 10.1097/MEG.0000000000002635
Yamashita S, Kishino T, Takahashi T, Shimazu T, Charvat H, Kakugawa Y, et al. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proc Natl Acad Sci U S A. 2018;115(6):1328–33.
pubmed: 29358395
pmcid: 5819434
doi: 10.1073/pnas.1717340115
Xie L, Zhang Z, Tan Z, He R, Zeng X, Xie Y, et al. MicroRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer. Mol Cell Biochem. 2014;392(1–2):153–9.
pubmed: 24658854
doi: 10.1007/s11010-014-2028-0
Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 2012;61(2):278–89.
pubmed: 21672940
doi: 10.1136/gut.2011.239145
Liu F, Hu H, Zhao J, Zhang Z, Ai X, Tang L, et al. miR-124-3p acts as a potential marker and suppresses tumor growth in gastric cancer. Biomed Rep. 2018;9(2):147–55.
pubmed: 30013778
pmcid: 6036824
Ando T, Yoshida T, Enomoto S, Asada K, Tatematsu M, Ichinose M, et al. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer. 2009;124(10):2367–74.
pubmed: 19165869
doi: 10.1002/ijc.24219
Song MA, Seffernick AE, Archer KJ, Mori KM, Park SY, Chang L, et al. Race/ethnicity-associated blood DNA methylation differences between Japanese and European American women: an exploratory study. Clin Epigenetics. 2021;13(1):188.
pubmed: 34635168
pmcid: 8507376
doi: 10.1186/s13148-021-01171-w
Pimentel-Nunes P, Libânio D, Bastiaansen BAJ, Bhandari P, Bisschops R, Bourke MJ, et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) Guideline—update 2022. Endoscopy. 2022;54(6):591–622.
pubmed: 35523224
doi: 10.1055/a-1811-7025
Dietrich D, Uhl B, Sailer V, Holmes EE, Jung M, Meller S, et al. Improved PCR performance using template DNA from formalin-fixed and paraffin-embedded tissues by overcoming PCR inhibition. PLoS ONE. 2013;8(10):e77771.
pubmed: 24155973
pmcid: 3796491
doi: 10.1371/journal.pone.0077771
Andersson D, Akrap N, Svec D, Godfrey TE, Kubista M, Landberg G, et al. Properties of targeted preamplification in DNA and cDNA quantification. Expert Rev Mol Diagn. 2015;15(8):1085–100.
pubmed: 26132215
pmcid: 4673511
doi: 10.1586/14737159.2015.1057124
Takeuchi C, Yamashita S, Liu Y-Y, Takeshima H, Sasaki A, Fukuda M, et al. Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation. Gut. 2024;73(2):255–67.
pubmed: 37751933
doi: 10.1136/gutjnl-2023-329492