Lynch Syndrome X-Talk of Enteral Mucosa With Immune System

Recruiting

• Conditions: 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

• Registration Number: NCT06708429
• Lead Sponsor: San Raffaele University

Brief Summary

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

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.

Study Timeline

• Study Start: 2023-06-01
• Status Verified: 2024-11
• Study First Submitted: 2024-11-25
• Study First Submitted QC: 2024-11-25
• Study First Posted: 2024-11-27
• Last Update Submitted: 2024-11-27
• Last Update Posted: 2024-12-02
• Primary Completion: 2033-06-01
• Study Completion: 2034-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Sensitivity	Through study completion, an average of 1 year	True positive rate: the probability of a positive test result, conditioned on the individual truly being positive

Secondary Outcome Measures

Name	Time	Method
Specificity	Through study completion, an average of 1 year	True negative rate: the probability of a negative test result, conditioned on the individual truly being negative
Proportion of correct predictions (true positives and true negatives) among the total number of cases (i.e., accuracy)	Through study completion, an average of 1 year	A measure of trueness: proportion of correct predictions (both true positives and true negatives) among the total number of cases examined
Prevalence of anti-frame-shift peptide antibodies positivity in blood sample	Through study completion, an average of 1 year	The proportion of individuals who have detectable levels of antibodies against frame shift peptides in their blood, conditioned on the individual truly being positive
Tumor microbiome analysis	Through study completion, an average of 1 year	A comprehensive analysis of the tumor microbiome to identify high-risk patients for colorectal cancer onset
Immuno-environmental tumor signature	Through study completion, an average of 1 year	A comprehensive evaluation of the differential expression of immunosuppressive myeloid-related signatures in colorectal lesions compared to healthy mucosa of patients with Lynch syndrome.; A comprehensive evaluation of the differential expression of immunosuppressive myeloid-related signatures in the blood of individuals with Lynch syndrome, with vs. without colorectal cancer
Exposure analysis	Through study completion, an average of 1 year	A comprehensive evaluation of the environmental exposure analysis on the hair matrix of individuals with Lynch syndrome, with vs. without colorectal cancer

Trial Locations

Locations (5)

Beckman Research Institute at City of Hope; 🇺🇸 Monrovia, California, United States

Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital; 🇮🇹 Milan, Lombardia, Italy

Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Nazionale Tumori; 🇮🇹 Milan, MI, Italy

Dipartimento di controllo qualità e rischio chimico biologico, AOOR Villa Sofia Cervello; 🇮🇹 Palermo, PM, Italy

Chirurgia Generale, Azienda Ospedaliero Universitaria di Cagliari; 🇮🇹 Cagliari, Italy