Gastrectomy for Gastric CancerEMBRACE-hGCNCT06982768
How Epigenetic Changes in hMLH1 Connect Lab Research With Diagnosis in Gastric Cancer
An observational study of Gastrectomy for Gastric Cancer and Gastrectomy, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastrectomy for Gastric Cancer, Gastrectomy, MLH1 Gene Mutation
- How many people
- 245 participants
- Where
- 1 siteItaly
- Study dates
- 1 Sep 2024to 31 Dec 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with Stage I to IV gastric cancer
Who may be able to join
- 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).
Who cannot join
- Patients with missing immunohistochemistry evaluation for the expression of the components of the MMR complex (MLH1, PMS2, MSH2, and MSH6).
Trial locations and contacts
1 site in 1 country.
Italy1 site
UOC Chirurgia Generale 1 - Fondazione Policlinico Universitario A. Gemelli IRCCS
Rome, 00168
About this study
Official title: Epigenetic Mechanisms Bridging Research and Clinical Examination in hMLH1 Hypermethylated Gastric Cancer
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.
- Medical subject headings
- Stomach Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Through study completion, an average of 1 year
Secondary outcomes (1)
Develop a predictive tool to categorize patients
Develop a predictive tool to categorize patients based on their expected responsiveness to specific chemotherapy or biological therapy regimens.
Measured: Through study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2025
- Study start1 Sep 2024
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Gastrectomy for Gastric CancerStudies of the same condition, open and under way.
- More trials run by Fondazione Policlinico Universitario Agostino Gemelli IRCCSThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 245 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Annamaria Agnes, Principal investigator, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06982768
- Sponsor's protocol ID
- 6212
- Acronym
- EMBRACE-hGC
- Status last verified
- Jul 2026
- First submitted
- 5 May 2025
- Last updated
- 23 Jul 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 16760303Bonneville 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.
PubMed 29850653Chistiakov 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.
PubMed 27774908Bouyahya 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.
PubMed 35327559Kim 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.
PubMed 23266441Maio 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.
PubMed 35680043Wu Q, Ni X. ROS-mediated DNA methylation pattern alterations in carcinogenesis. Curr Drug Targets. 2015;16(1):13-9. doi: 10.2174/1389450116666150113121054.
PubMed 25585126An 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.
PubMed 15701853Toyota 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.
PubMed 10554013Fleisher 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.
PubMed 10070967Nan 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.
PubMed 15991278Cancer 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.
PubMed 25079317Dugue 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.
PubMed 33442664
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Epigenetic Mechanisms Bridging Research and Clinical Examination in hMLH1 Hypermethylated Gastric Cancer
- ClinicalTrials.gov ID
- NCT06982768
- Acronym / sponsor ID
- EMBRACE-hGC / 6212
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 245 participants (estimated)
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
- Study start
- 1 Sep 2024 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 21 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with Stage I to IV gastric cancer
Key inclusion criteria (4 listed)
- 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).
Key exclusion criteria (1 listed)
- Patients with missing immunohistochemistry evaluation for the expression of the components of the MMR complex (MLH1, PMS2, MSH2, and MSH6).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Correlation between the occurrence of hMLH1 hypermethylated gastric cancer and the clinicopathologic characteristics of patients
Time frame: Through study completion, an average of 1 year
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.
1 secondary outcome
Develop a predictive tool to categorize patients
Time frame: Through study completion, an average of 1 year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2026.
- Background: PubMed 16760303Ottini 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.
- Background: PubMed 29850653Bonneville 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.
- Background: PubMed 27774908Chistiakov 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.
- Background: PubMed 35327559Bouyahya 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.
- Background: PubMed 23266441Kim 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.
- Background: PubMed 35680043Maio 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.
- Background: PubMed 25585126Wu Q, Ni X. ROS-mediated DNA methylation pattern alterations in carcinogenesis. Curr Drug Targets. 2015;16(1):13-9. doi: 10.2174/1389450116666150113121054.
- Background: PubMed 15701853An 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.
- Background: PubMed 10554013Toyota 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.
- Background: PubMed 10070967Fleisher 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.
- Background: PubMed 15991278Nan 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.
- Background: PubMed 25079317Cancer 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Annamaria Agnes principal investigator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gastrectomy for Gastric Cancer and Gastrectomy, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 23 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Correlation between the occurrence of hMLH1 hypermethylated gastric cancer and the clinicopathologic characteristics of patients (time frame: Through study completion, an average of 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06982768, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2026.