Lynch Syndrome X-Talk of Enteral Mucosa With Immune System

NCT06708429 | Recruiting

• 1 other identifier: LYNX EYE 2023
• Study Type: observational
• Target: 300
• Locations: 2 countries
• Sites: 5

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.

Conditions

Lynch Syndrome I (Site-specific Colonic Cancer); Lynch Syndrome; Lynch Syndrome I; Lynch Syndrome II; 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

Outcome Measures

Primary Outcomes (1)

• Sensitivity

  True positive rate: the probability of a positive test result, conditioned on the individual truly being positive

  Through study completion, an average of 1 year

Secondary Outcomes (6)

• Specificity

  Through study completion, an average of 1 year

• 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

• Prevalence of anti-frame-shift peptide antibodies positivity in blood sample

  Through study completion, an average of 1 year

• Tumor microbiome analysis

  Through study completion, an average of 1 year

• Immuno-environmental tumor signature

  Through study completion, an average of 1 year

Study Arms (14)

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

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

Lynch syndrome (MLH1), with colorectal cancer or 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 have colorectal cancer or an adenoma at the time of colonoscopy evaluation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Non-Lynch syndrome, with colorectal cancer

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

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

Non-Lynch syndrome, with high-risk adenomas

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

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

Non-Lynch syndrome, with low-risk adenomas

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

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

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

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

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

Interventions

LYNX EYE (Lynch syndrome X-Talk of Enteral mucosa with Immune System) DIAGNOSTIC_TEST

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)

Lynch syndrome (MLH1), with colorectal cancer or advanced adenomas; Lynch syndrome (MLH1), without colorectal cancer and without advanced adenomas; Lynch syndrome (MSH2), with colorectal cancer or advanced adenomas; Lynch syndrome (MSH2), without colorectal cancer and without advanced adenomas; Lynch syndrome (MSH2, exon 8 deletion), with colorectal cancer or advanced adenomas; Lynch syndrome (MSH2, exon 8 deletion), without colorectal cancer and without advanced adenomas; Lynch syndrome (MSH6), with colorectal cancer or advanced adenomas; Lynch syndrome (MSH6, without colorectal cancer and without advanced adenomas; Lynch syndrome (PMS2), with colorectal cancer or advanced adenomas; Lynch syndrome (PMS2), without colorectal cancer and without advanced adenomas; Non-Lynch syndrome, with colorectal cancer; Non-Lynch syndrome, with high-risk adenomas; Non-Lynch syndrome, with low-risk adenomas; Non-Lynch syndrome, without colorectal cancer and without colorectal adenomas

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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
• 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 \[PREMM5 is an online, free-to-use, clinical prediction algorithm that estimates the cumulative probability of an individual carrying a germline mutation in the mismatch repair genes responsible for Lynch syndrome\].

You may not qualify if:

• 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

Sponsors & Collaborators

• San Raffaele University: lead

Study Sites (5)

Beckman Research Institute at City of Hope

Monrovia, California, 91016, United States

RECRUITING

Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital

Milan, Lombardy, 20132, Italy

RECRUITING

Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Nazionale Tumori

Milan, MI, Italy

RECRUITING

Dipartimento di controllo qualità e rischio chimico biologico, AOOR Villa Sofia Cervello

Palermo, PM, Italy

RECRUITING

Chirurgia Generale, Azienda Ospedaliero Universitaria di Cagliari

Cagliari, Italy

RECRUITING

Related Publications (24)

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  PMID: 25673086 BACKGROUND

• Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG, Buchanan DD, Clendenning M, Rosty C, Ahnen DJ, Thibodeau SN, Casey G, Gallinger S, Le Marchand L, Haile RW, Potter JD, Zheng Y, Lindor NM, Newcomb PA, Hopper JL, MacInnis RJ. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):404-412. doi: 10.1158/1055-9965.EPI-16-0693. Epub 2016 Oct 31.

  PMID: 27799157 BACKGROUND

• Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H, Snaebjornsson P, Masson G, Weng D, Arngrimsson R, Kehr B, Yilmaz A, Haraldsson S, Sulem P, Stefansson T, Shields PG, Sigurdsson F, Bekaii-Saab T, Moller PH, Steinarsdottir M, Alexiusdottir K, Hitchins M, Pritchard CC, de la Chapelle A, Jonasson JG, Goldberg RM, Stefansson K. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun. 2017 May 3;8:14755. doi: 10.1038/ncomms14755.

  PMID: 28466842 BACKGROUND

• Engel C, Vasen HF, Seppala T, Aretz S, Bigirwamungu-Bargeman M, de Boer SY, Bucksch K, Buttner R, Holinski-Feder E, Holzapfel S, Huneburg R, Jacobs MAJM, Jarvinen H, Kloor M, von Knebel Doeberitz M, Koornstra JJ, van Kouwen M, Langers AM, van de Meeberg PC, Morak M, Moslein G, Nagengast FM, Pylvanainen K, Rahner N, Renkonen-Sinisalo L, Sanduleanu S, Schackert HK, Schmiegel W, Schulmann K, Steinke-Lange V, Strassburg CP, Vecht J, Verhulst ML, de Vos Tot Nederveen Cappel W, Zachariae S, Mecklin JP, Loeffler M; German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and the Finnish Lynch Syndrome Registry. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies. Gastroenterology. 2018 Nov;155(5):1400-1409.e2. doi: 10.1053/j.gastro.2018.07.030. Epub 2018 Jul 29.

  PMID: 30063918 BACKGROUND

• Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rodland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen J, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Frayling IM, Plazzer JP, Pylvanainen K, Sampson JR, Capella G, Mecklin JP, Moslein G; Mallorca Group (http://mallorca-group.eu). Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017 Mar;66(3):464-472. doi: 10.1136/gutjnl-2015-309675. Epub 2015 Dec 9.

  PMID: 26657901 BACKGROUND

• Seppala T, Pylvanainen K, Evans DG, Jarvinen H, Renkonen-Sinisalo L, Bernstein I, Holinski-Feder E, Sala P, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rodland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen J, Jenkins M, Genuardi M, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Frayling IM, Plazzer JP, Sampson JR, Capella G, Moslein G, Mecklin JP, Moller P; Mallorca Group. Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report. Hered Cancer Clin Pract. 2017 Oct 10;15:18. doi: 10.1186/s13053-017-0078-5. eCollection 2017.

  PMID: 29046738 BACKGROUND

• Mecklin JP, Aarnio M, Laara E, Kairaluoma MV, Pylvanainen K, Peltomaki P, Aaltonen LA, Jarvinen HJ. Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology. 2007 Oct;133(4):1093-8. doi: 10.1053/j.gastro.2007.08.019. Epub 2007 Aug 14.

  PMID: 17919485 BACKGROUND

• Vasen HF, Abdirahman M, Brohet R, Langers AM, Kleibeuker JH, van Kouwen M, Koornstra JJ, Boot H, Cats A, Dekker E, Sanduleanu S, Poley JW, Hardwick JC, de Vos Tot Nederveen Cappel WH, van der Meulen-de Jong AE, Tan TG, Jacobs MA, Mohamed FL, de Boer SY, van de Meeberg PC, Verhulst ML, Salemans JM, van Bentem N, Westerveld BD, Vecht J, Nagengast FM. One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology. 2010 Jun;138(7):2300-6. doi: 10.1053/j.gastro.2010.02.053. Epub 2010 Mar 2.

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• Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, De La Chapelle A, Mecklin JP. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000 May;118(5):829-34. doi: 10.1016/s0016-5085(00)70168-5.

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• Engel C, Rahner N, Schulmann K, Holinski-Feder E, Goecke TO, Schackert HK, Kloor M, Steinke V, Vogelsang H, Moslein G, Gorgens H, Dechant S, von Knebel Doeberitz M, Ruschoff J, Friedrichs N, Buttner R, Loeffler M, Propping P, Schmiegel W; German HNPCC Consortium. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol. 2010 Feb;8(2):174-82. doi: 10.1016/j.cgh.2009.10.003. Epub 2009 Oct 14.

  PMID: 19835992 BACKGROUND

• Ahadova A, von Knebel Doeberitz M, Blaker H, Kloor M. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer. 2016 Oct;15(4):579-86. doi: 10.1007/s10689-016-9899-z.

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Biospecimen

Retention: SAMPLES WITH DNA

Formalin-fixed, paraffine embedded mucosal samples Formalin-fixed, paraffine embedded tumor samples Hair matrix Plasma Serum

MeSH Terms

Conditions

Colorectal Neoplasms, Hereditary Nonpolyposis; Lynch Syndrome II; Lynch syndrome I (site-specific colonic cancer); Neoplastic Syndromes, Hereditary; Colorectal Neoplasms; Endometrial Neoplasms; Turcot syndrome

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Rectal Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Giulia Martina Cavestro, MD, PhD

  IRCCS San Raffaele Scientific Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giulia Martina Cavestro, MD, PhD

CONTACT

0226436303; cavestro.giuliamartina@hsr.it

Alessandro Mannucci, MD

CONTACT

0226436303; mannucci.alessandro@hsr.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2024
• First Posted: November 27, 2024
• Study Start: June 1, 2023
• Primary Completion (Estimated): June 1, 2033
• Study Completion (Estimated): June 1, 2034
• Last Updated: April 24, 2026

Record last verified: 2026-04

Locations

US (1); IT (4)