Home
Clinical Trials
Lynch Syndrome X-Talk of Ente...

Lynch Syndrome X-Talk of Enteral Mucosa With Immune System

Last Updated: 2024-12-02

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

RECRUITING

Total Enrollment

300 participants

Study Classification

OBSERVATIONAL

Study Start Date

2023-06-01

Study Completion Date

2034-06-01

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

Lynch syndrome (OMIM #120435) is the most common dominantly inherited colorectal cancer syndrome with an estimated prevalence of 1:270 individuals. It increases the lifetime risk of colorectal and endometrial cancer primarily, but it is associated with a high risk of other cancers (pancreas, stomach, ovarian, central nervous system, skin, among others). It is caused by a germline mutation in one of four DNA mismatch repair genes or a terminal deletion of the MSH2-adjacent gene EpCAM.

Despite adherence to cancer surveillance programs, many patients still develop colorectal cancer and endometrial cancer. The Prospective Lynch Syndrome Database (PLSD) suggests that more frequent surveillance intervals do not significantly improve cancer risk reduction. The PLSD also revealed that the incidence of colorectal cancer in MLH1 and MSH2 carriers was even higher than previously expected, reaching as high as 41-36% among MLH1 carriers, regardless of ethnic background. The development of colorectal cancer despite surveillance is an unresolved question. Therefore, there is an unmet need for effective cancer prevention strategies.

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

The risk of developing colorectal cancer in individuals with Lynch syndrome remains high despite endoscopic surveillance.

In Lynch Syndrome, the cancer-formation process is characterized by the development of immunogenic neo-antigens in the mucosa. These neoantigens, called frame-shift peptides, can be recognized by the adaptive immune systems, and trigger the formation of antibodies against them (termed anti-frame-shift peptides antibodies). Anti-frame-shift peptide antibodies have been reported in some Lynch syndrome patients (defined dichotomously as the presence vs absence of anti-frame-shift peptide antibodies). This study hypothesizes that anti-frame-shift peptide antibodies represent an early biomarker of cancer development in Lynch syndrome. These anti-frame-shift peptide antibodies may be used to identify early patients at the highest risk of developing colorectal cancer. All studies on anti-frame-shift peptide antibodies have had a cross-sectional design, while a retro-prospective design would be desirable to understand the interaction between the mucosa and the mucosa-associated immune system. There is also limited evidence that individuals with Lynch syndrome develop mismatch repair-deficient crypts before colorectal cancer development. The development of interval colorectal cancers may require specific biological processes. Understanding the biological processes underlying these interval colorectal cancers would help define targets of innovative therapies to prevent colorectal cancer (including but not limited to chemoprevention strategies and cancer vaccines). The interactions between the mucosa immune surveillance and the colonic epithelium are the cornerstone to answer such questions. Finally, the development of gastric cancer via non-canonical pathways (non-Correa, non-HPylori) demands a better understanding of the pathogenesis in individuals with Lynch syndrome.

MicroRNA (miRNA) expression has been shown to have diagnostic, prognostic, and therapeutic potential. While they offer high detection sensitivity, the heterogeneity limits their detection accuracy. Exosomes are excreted by cancer cells and possess specific exosomal miRNA signatures. Since circulating cell-free miRNAs offer excellent sensitivity but may suffer from inadequate specificity, while exosomal miRNAs are highly tissue-specific but might lack sensitivity, a combination of these biomarkers could offer an optimal combination of sensitivity and specificity. 98.5% of the total DNA is non-coding regions with roles in gene regulation, alternative splicing, interaction with transcription factors, and sequences capable of moving around the genome and promoting carcinogenesis. The understanding of non-coding DNA seems to be important in cancer early diagnosis.

Lynch syndrome-associated colorectal cancers are high immunogenic lesions with abundant lymphocyte infiltration. This study aims to develop an extensive profile of the immunosuppressive and regulatory cellular population in blood and tumor sites to identify patients with higher risks of cancer development.

Recent data have demonstrated the presence of intratumor bacteria in both cancer and immune cells. Therefore, this study also aims to analyze in colonic biopsies from Lynch syndrome patients with- and without tumors the presence of microbiota as an early signature for carcinogenesis.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Lynch Syndrome Lynch Syndrome I Lynch Syndrome II Lynch Syndrome I (Site-specific Colonic Cancer) HNPCC HNPCC Gene Mutation Hereditary Cancer Syndrome Hereditary Cancer MLH1 Gene Mutation MLH1 Gene Deletion+Duplication MLH1 Loss of Expression MLH1 Gene Inactivation MSH2 Gene Mutation MSH2 Gene Deletion+Duplication MSH2 Loss of Expression MSH2 Gene Inactivation MSH6 Gene Mutation MSH6 Loss of Expression MSH6 Gene Inactivation PMS2 Gene Mutation PMS2 Gene Inactivation PMS2 Loss of Expression

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Lynch syndrome (MLH1), without colorectal cancer and without advanced adenomas

A cohort of individuals with a germline pathogenic variant in the MLH1 gene, that confers a diagnosis of Lynch syndrome, who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation