How Epigenetic Changes in hMLH1 Connect Lab Research With Diagnosis in Gastric Cancer
NCT ID: NCT06982768
Last Updated: 2026-01-02
Study Results
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Basic Information
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RECRUITING
245 participants
OBSERVATIONAL
2024-09-01
2026-04-30
Brief Summary
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Gastric cancer has been classified in different molecular phenotypes based on genetic and epigenetic characteristics. One of these subtypes is characterized by a high grade of microsatellite instability (MSI-H). In gastric cancer, the MSI-H status is mostly caused by methylation of the hMLH1 gene promoter (between 71% and 78%), that is also considered the representative of a gastric-specific CpG island methylation pattern (CIMP). Gastric cancer with hMLH1 hypermethylation is frequently expressed in the MSI-H phenotype but also reported in the MSI-L type. Hypermethylation has been associated with advanced age, dietary habits, smoking and alcohol consumption. Moreover, other studies on GI cancer (colorectal, rectal and gastric) have associated hMLH1 hypermethylation with decreased levels of folate, vitamin C and niacin. Last, increased oxidative stress has been proposed as one of the possible initiators of cancer development and progression through epigenetic mechanism as hypermethylation. From a clinical standpoint, MSI-H gastric cancers have been associated with increased resistance to standard chemotherapy and increased immunogenicity, representing a hypothetic ideal target to immunotherapy, that has documented clinical efficacy for this subtype. However, some authors have suggested that MSI-H GCs without hMLH1 hypermethylation and GCs with hMLH1 hypermethylation could be different in terms of clinicopathologic characteristics and biological behavior. In addition, the specific role of hMLH1 hypermethylation in resistance to standard chemotherapy is unknown, as well as its potential adjunctive role in the chemoresistance of hypermethylated - but MSI-L - tumors.
Identifying risk factors for hMLH1 hypermethylated GC could have relevant implications in terms of disease prevention and even reversal of the hypermethylation mechanisms through natural as well as synthetic compounds. It could also identify a predictive tool to better stratify patients for expected sensitivity to specific chemotherapy (or biological therapy) regimens. Therefore, this preliminary study aims to determine if the development of hMLH1-methylated GC is associated with specific clinicopathologic characteristics and environmental habits. It also aims to report on the biological behavior of these tumors, as well as on their chemosensitivity to platin-based chemotherapy regimens.
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Detailed Description
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Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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No altered expression of the components of the MMR complex
Patients without altered expression of the components of the MMR complex
No interventions assigned to this group
Altered expression of the components of the MMR complex
Patients with altered expression of the components of the MMR complex
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* Surgery performed at the General Surgery Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS.
* Procedures conducted between January 2017 and August 2023.
* Only patients who have already undergone immunohistochemistry evaluation for expression of the components of the MMR complex (MLH1, PMS2, MSH2, and MSH6).
Exclusion Criteria
18 Years
ALL
No
Sponsors
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Fondazione Policlinico Universitario Agostino Gemelli IRCCS
OTHER
Responsible Party
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Principal Investigators
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Annamaria Agnes
Role: PRINCIPAL_INVESTIGATOR
Fondazione Policlinico Universitario A. Gemelli, IRCCS
Locations
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UOC Chirurgia Generale 1 - Fondazione Policlinico Universitario A. Gemelli IRCCS
Rome, , Italy
Countries
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Central Contacts
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Facility Contacts
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Annamaria Agnes
Role: primary
References
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Ottini L, Falchetti M, Lupi R, Rizzolo P, Agnese V, Colucci G, Bazan V, Russo A. Patterns of genomic instability in gastric cancer: clinical implications and perspectives. Ann Oncol. 2006 Jun;17 Suppl 7:vii97-102. doi: 10.1093/annonc/mdl960.
Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, Reeser JW, Yu L, Roychowdhury S. Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 2017;2017:PO.17.00073. doi: 10.1200/PO.17.00073. Epub 2017 Oct 3.
Chistiakov DA, Myasoedova VA, Orekhov AN, Bobryshev YV. Epigenetically Active Drugs Inhibiting DNA Methylation and Histone Deacetylation. Curr Pharm Des. 2017;23(8):1167-1174. doi: 10.2174/1381612822666161021110827.
Bouyahya A, Mechchate H, Oumeslakht L, Zeouk I, Aboulaghras S, Balahbib A, Zengin G, Kamal MA, Gallo M, Montesano D, El Omari N. The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions. Biomolecules. 2022 Feb 25;12(3):367. doi: 10.3390/biom12030367.
Kim KJ, Lee TH, Cho NY, Yang HK, Kim WH, Kang GH. Differential clinicopathologic features in microsatellite-unstable gastric cancers with and without MLH1 methylation. Hum Pathol. 2013 Jun;44(6):1055-64. doi: 10.1016/j.humpath.2012.09.009. Epub 2012 Dec 23.
Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH, Oh DY, Gottfried M, Xu L, Jin F, Norwood K, Marabelle A. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022 Sep;33(9):929-938. doi: 10.1016/j.annonc.2022.05.519. Epub 2022 Jun 6.
Wu Q, Ni X. ROS-mediated DNA methylation pattern alterations in carcinogenesis. Curr Drug Targets. 2015;16(1):13-9. doi: 10.2174/1389450116666150113121054.
An C, Choi IS, Yao JC, Worah S, Xie K, Mansfield PF, Ajani JA, Rashid A, Hamilton SR, Wu TT. Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):656-63.
Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB, Issa JP. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999 Nov 1;59(21):5438-42.
Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, Zou TT, Abraham JM, Kong D, Smolinski KN, Shi YQ, Rhyu MG, Powell SM, James SP, Wilson KT, Herman JG, Meltzer SJ. Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res. 1999 Mar 1;59(5):1090-5.
Nan HM, Song YJ, Yun HY, Park JS, Kim H. Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer. World J Gastroenterol. 2005 Jul 7;11(25):3834-41. doi: 10.3748/wjg.v11.i25.3834.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014 Sep 11;513(7517):202-9. doi: 10.1038/nature13480. Epub 2014 Jul 23.
Dugue PA, Bassett JK, Wong EM, Joo JE, Li S, Yu C, Schmidt DF, Makalic E, Doo NW, Buchanan DD, Hodge AM, English DR, Hopper JL, Giles GG, Southey MC, Milne RL. Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study. JNCI Cancer Spectr. 2020 Nov 16;5(1):pkaa109. doi: 10.1093/jncics/pkaa109. eCollection 2021 Feb.
Other Identifiers
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6212
Identifier Type: -
Identifier Source: org_study_id
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