Impact of Immune-surveillance on the Development of Colorectal Cancer in Patients With Lynch Syndrome
San Raffaele University
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.
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-s…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- Not specified
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 s…
Interventions
- Diagnostic TestLYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System)
A combination of blood-based, mucosal-based, and hair-based analyses that evaluate the presence and the expression of: * a set of microRNAs (blood) * antibodies anti-frame shift peptides (blood) * mucosal-resident bacteria (healthy mucosa and cancer) * environmental exposure to potential carcinogens (hair matrix)
Locations (5)
- Beckman Research Institute at City of HopeMonrovia, California
- Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele HospitalMilan, Lombardy
- Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Nazionale TumoriMilan, MI
- Dipartimento di controllo qualità e rischio chimico biologico, AOOR Villa Sofia CervelloPalermo, PM
- Chirurgia Generale, Azienda Ospedaliero Universitaria di CagliariCagliari