Clinical trial NCT06708429: Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
Official title: Impact of Immune-surveillance on the Development of Colorectal Cancer in Patients With Lynch Syndrome
Study type: OBSERVATIONAL
Overall status: 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
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
Keywords: Colorectal cancer
Endometrial cancer
Lynch syndrome-associated cancer
Surveillance
Cancer surveillance
Immune profile
Immune escape
Mismatch repair deficiency
Microbiota
Liquid biopsy
MicroRNA
Transcriptomic
Frame shift peptides
MLH1
MSH2
EpCAM
MSH6
PMS2
Hair matrix
Lead sponsor: San Raffaele University
Sponsor class: OTHER
First posted: 2024-11-27
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will enroll patients with and without Lynch syndrome, with and without colorectal cancer or colorectal adenomas.

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.

Eligibility criteria: Inclusion Criteria (for participants with Lynch syndrome):

* Age ≥18 years
* All sexes eligible
* Established diagnosis of Lynch syndrome performed as part of clinical practice, with a germline pathogenic/likely pathogenic variant in one of the following genes: MLH1, MSH2, MSH6, PMS2, and EpCAM
* Subjects with Lynch syndrome undergoing surveillance gastrointestinal endoscopy and/or surgery according to clinical practice
* Fertile patients (both males and females) are eligible
* Lactating women are eligible

Inclusion Criteria (for participants without Lynch syndrome):

* Age ≥18 years
* All sexes eligible
* Patients with sporadic colorectal lesions, including colorectal cancer and colorectal adenomas
* Healthy controls without colorectal cancer or adenomas undergoing lower gastrointestinal endoscopy for abdominal pain
* PREMM5 \< 2.5 \[PREMM5 is an online, free-to-use, clinical prediction algorithm that estimates the cumulative probability of an individual carrying a germline mutation in the mismatch repair genes responsible for Lynch syndrome\].

Exclusion Criteria (for participants with or without Lynch syndrome):

* Age \< 18 years;
* Diseases that are known to predispose to colorectal cancer (personal past or recent history of inflammatory bowel disease);
* Patients unable/unwilling to provide consent;
* Pregnancy

Primary outcomes:
measure: Sensitivity
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
measure: Specificity
timeFrame: Through study completion, an average of 1 year
measure: Proportion of correct predictions (true positives and true negatives) among the total number of cases (i.e., accuracy)
timeFrame: Through study completion, an average of 1 year
measure: Prevalence of anti-frame-shift peptide antibodies positivity in blood sample
timeFrame: Through study completion, an average of 1 year
measure: Tumor microbiome analysis
timeFrame: Through study completion, an average of 1 year
measure: Immuno-environmental tumor signature
timeFrame: Through study completion, an average of 1 year
measure: Exposure analysis
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Monrovia
country: United States
facility: Beckman Research Institute at City of Hope
state: California
city: Milan
country: Italy
facility: Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital
state: Lombardia
city: Milan
country: Italy
facility: Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Nazionale Tumori
state: MI
city: Palermo
country: Italy
facility: Dipartimento di controllo qualità e rischio chimico biologico, AOOR Villa Sofia Cervello
state: PM
city: Cagliari
country: Italy
facility: Chirurgia Generale, Azienda Ospedaliero Universitaria di Cagliari
Study officials:
affiliation: IRCCS San Raffaele Scientific Institute
name: Giulia Martina Cavestro, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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