Lynch Syndrome X-Talk of Enteral Mucosa With Immune System (LYNX-EYE)

San Raffaele University

Status: Enrolling

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

Treatments: Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Study type: Observational

Funder types: Other

Identifiers

NCT06708429

LYNX EYE 2023

Details and patient eligibility

About

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.

Full 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.

Enrollment: 300 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

300 participants in 14 patient groups

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

Description:

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

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MLH1), with colorectal cancer or advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the MLH1 gene, that confers a diagnosis of Lynch syndrome, who are found to have colorectal cancer or an adenoma at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH2), without colorectal cancer and without advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the MSH2 gene, that confers a diagnosis of Lynch syndrome, who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH2), with colorectal cancer or advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the MSH2 gene, that confers a diagnosis of Lynch syndrome, who are found to have colorectal cancer or an adenoma at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH6, without colorectal cancer and without advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the MSH6 gene, that confers a diagnosis of Lynch syndrome, who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH6), with colorectal cancer or advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the MSH6 gene, that confers a diagnosis of Lynch syndrome, who are found to have colorectal cancer or an adenoma at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (PMS2), without colorectal cancer and without advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the PMS2 gene, that confers a diagnosis of Lynch syndrome, who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (PMS2), with colorectal cancer or advanced adenomas

Description:

A cohort of individuals with a germline pathogenic variant in the PMS2 gene, that confers a diagnosis of Lynch syndrome, who are found to have colorectal cancer or an adenoma at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH2, exon 8 deletion), without colorectal cancer and without advanced adenomas

Description:

A cohort of individuals with a germline pathogenic exon 8 deletion in the MSH2 gene, that confers a diagnosis of Lynch syndrome, who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Lynch syndrome (MSH2, exon 8 deletion), with colorectal cancer or advanced adenomas

Description:

A cohort of individuals with a germline pathogenic exon 8 deletion in the MSH2 gene, that confers a diagnosis of Lynch syndrome, who are found to have colorectal cancer or an adenoma at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Non-Lynch syndrome, with colorectal cancer

Description:

A cohort of individuals without a germline pathogenic variant in any of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2), who are found to have colorectal cancer at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Non-Lynch syndrome, with high-risk adenomas

Description:

A cohort of individuals without a germline pathogenic variant in any of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2), who are found to have high-risk adenomas at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Non-Lynch syndrome, with low-risk adenomas

Description:

A cohort of individuals without a germline pathogenic variant in any of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2), who are found to have low-risk adenomas at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)

Non-Lynch syndrome, without colorectal cancer and without colorectal adenomas

Description:

A cohort of individuals without a germline pathogenic variant in any of the mismatch repair genes (MLH1, MSH2, MSH6, PMS2), who are found to be cancer-free and adenoma-free at the time of colonoscopy evaluation

Treatment:

Diagnostic Test: LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)