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

NCT06982768 · Status: RECRUITING · Type: OBSERVATIONAL · Enrollment: 245

Last updated 2026-01-02

No results posted yet for this study

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

Sponsors & Collaborators

  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS

    lead OTHER

Principal Investigators

  • Annamaria Agnes · Fondazione Policlinico Universitario A. Gemelli, IRCCS

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2024-09-01
Primary Completion
2025-12-31
Completion
2026-04-30

Countries

  • Italy

Study Locations

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Entities

Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT06982768 on ClinicalTrials.gov