How Epigenetic Changes in hMLH1 Connect Lab Research With Diagnosis in Gastric Cancer

NCT06982768 | Recruiting

• 1 other identifier: 6212
• Study Type: observational
• Target: 245
• Locations: 1 country
• Sites: 1

Brief Summary

DNA methylation is one of the key mechanisms that are thought to underlie the association between aging and cancer. Several methylation-based measures of biological aging have been developed and have demonstrated an association with mortality and, in some cases, with cancer incidence. Accordingly, CpG promoter hypermethylation is a well-known mechanism of gene inactivation in carcinogenesis. 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.

Conditions

Gastrectomy for Gastric Cancer; Gastrectomy; MLH1 Gene Mutation; Gastric Cancer

Outcome Measures

Primary Outcomes (1)

• Correlation between the occurrence of hMLH1 hypermethylated gastric cancer and the clinicopathologic characteristics of patients

  The primary objective of this study is to explore the correlation between the occurrence of hMLH1 hypermethylated gastric cancer and the clinicopathologic characteristics of patients, thereby identifying potential predisposing factors.

  Through study completion, an average of 1 year

Secondary Outcomes (1)

• Develop a predictive tool to categorize patients

  Through study completion, an average of 1 year

Study Arms (2)

Altered expression of the components of the MMR complex

Patients with altered expression of the components of the MMR complex

No altered expression of the components of the MMR complex

Patients without altered expression of the components of the MMR complex

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with Stage I to IV gastric cancer

You may qualify if:

• Patients who underwent elective gastrectomy for Stage I-IV gastric cancer.
• 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).

You may not qualify if:

• \- Patients with missing immunohistochemistry evaluation for the expression of the components of the MMR complex (MLH1, PMS2, MSH2, and MSH6).

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

UOC Chirurgia Generale 1 - Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, 00168, Italy

RECRUITING

Related Publications (13)

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  PMID: 27774908 BACKGROUND

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  PMID: 35327559 BACKGROUND

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  PMID: 10070967 BACKGROUND

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  PMID: 33442664 BACKGROUND

MeSH Terms

Conditions

Stomach Neoplasms

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Study Officials

• Annamaria Agnes

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Annamaria Agnes

CONTACT

+39 0630167190; annamaria.agnes@policlinicogemelli.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 5, 2025
• First Posted: May 21, 2025
• Study Start: September 1, 2024
• Primary Completion: December 31, 2025
• Study Completion: April 30, 2026
• Last Updated: January 2, 2026

Record last verified: 2025-05

Locations

IT (1)