Clinical trial NCT06982768: How Epigenetic Changes in hMLH1 Connect Lab Research With Diagnosis in Gastric Cancer
Official title: Epigenetic Mechanisms Bridging Research and Clinical Examination in hMLH1 Hypermethylated Gastric Cancer
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Gastrectomy for Gastric Cancer
Gastrectomy
MLH1 Gene Mutation
Gastric Cancer
Lead sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sponsor class: OTHER
First posted: 2025-05-21
Enrollment: 245
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with Stage I to IV gastric cancer

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.


Eligibility criteria: Inclusion Criteria:

* 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).

Exclusion Criteria:

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

Primary outcomes:
measure: Correlation between the occurrence of hMLH1 hypermethylated gastric cancer and the clinicopathologic characteristics of patients
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
measure: Develop a predictive tool to categorize patients
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Rome
country: Italy
facility: UOC Chirurgia Generale 1 - Fondazione Policlinico Universitario A. Gemelli IRCCS
Study officials:
affiliation: Fondazione Policlinico Universitario A. Gemelli, IRCCS
name: Annamaria Agnes
role: PRINCIPAL_INVESTIGATOR
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