Lynch Syndrome X-Talk of Enteral Mucosa With Immune System

Официальное название

Impact of Immune-surveillance on the Development of Colorectal Cancer in Patients With Lynch Syndrome

Обзор

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.

Подробное описание

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.

Вмешательства

• Диагностический тест LYNX 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)

Первичные конечные точки

• Sensitivity [Срок оценки: Through study completion, an average of 1 year]

Вторичные конечные точки (6)

• Specificity [Срок оценки: 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) [Срок оценки: Through study completion, an average of 1 year]
• Prevalence of anti-frame-shift peptide antibodies positivity in blood sample [Срок оценки: Through study completion, an average of 1 year]
• Tumor microbiome analysis [Срок оценки: Through study completion, an average of 1 year]
• Immuno-environmental tumor signature [Срок оценки: Through study completion, an average of 1 year]
• Exposure analysis [Срок оценки: Through study completion, an average of 1 year]

Критерии участия

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Италия · 4 центра

• Gastronterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Hospital — Milan
• Dipartimento di Chirurgia Oncologica e Dipartimento di Oncologia Sperimentale Istituto Naz — Milan
• Dipartimento di controllo qualità e rischio chimico biologico, AOOR Villa Sofia Cervello — Palermo
• Chirurgia Generale, Azienda Ospedaliero Universitaria di Cagliari — Cagliari

США · 1 центр

• Beckman Research Institute at City of Hope — Monrovia

Публикации

• Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015 Mar;15(3):181-94. doi: 10.1038/nrc3878. Epub 2015 Feb 12. PMID 25673086
• 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 PMID 27799157
• 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 Lyn PMID 28466842
• 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- PMID 30063918
• 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 PMID 26657901
• 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 PMID 29046738
• 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
• 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 PMID 20206180

Идентификаторы

NCT: NCT06708429 · LYNX EYE 2023

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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