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The main aim of this study is to determine the prevalence of Muir-Torre syndrome (MTS) in the population of patients with Lynch syndrome (LS) confirmed by genetic analysis. Other aims include describing the dermatological clinical manifestations of these patients in order to describe any possible new cutaneous manifestations of this syndrome. Another aim is to use molecular biology (microsatellite instability) and immunohistochemistry to analyze non-sebaceous skin lesions and deep-seated tumors that do not belong to the narrow spectrum of Lynch syndrome, and determine whether their occurrence in these patients is related to the genetic syndrome. The follow-up of these tumors (screening for new tumors) in patients with SL, as recommended by the learned societies, will also be evaluated. Finally, a biobank of cutaneous and deep tumour lesions in paraffin (retrospective) and smears of cutaneous lesions and healthy tissue (prospective) will be set up.
Muir-Torre Syndrome (MTS) is an autosomal dominant disease described independently by Muir et al. in 1967 and Torre in 1968, defined by the association of a visceral tumor of the Lynch spectrum (colorectal, endometrial, urinary excretory tract, biliary tract, small intestine, stomach or glioblastoma carcinomas) and sebaceous skin tumors and/or multiple keratoacanthomas.
Histo-molecular examination of tumors for TMS/SL is based on 2 techniques, each focusing on a different aspect of TMS pathophysiology.
Immunohistochemistry (IHC) studies the presence of proteins from the MisMatch Repair (MMR) system in lesional tissues, and an absence of expression of one of these proteins is the physical translation of an abnormality in the MMR pathway, for which the presence of a constitutional mutation in one of the MMR system genes (MLH1, PMS2, MSH2, MSH6) is responsible. An IHC-deficient MMR phenotype (dMMR) results in a complete loss of expression of one or more MMR proteins in tumor cells, with expression maintained in "normal" cells (connective cells, immune cells, non-tumor epithelial cells).
Molecular biology or microsatellite instability (MSI) testing focuses on the molecular repercussions of MMR pathway failure. The aim of this technique is to determine the presence of microsatellite marker instability in tumor tissue. While for colorectal tumors, a comparative analysis of the patient's healthy tissue can be dispensed with, for other organs on the Lynch spectrum, including sebaceous tumors, a comparison with DNA from normal tissue can help interpret the results.
The incidence of TMS among patients with genetically proven SL is poorly known. Two studies have shown a prevalence of 9.2%, both involving American patients (1,2). These were 2 retrospective chart-based studies, the skin tumors not having been re-read for diagnostic confirmation.
These patients may also develop skin tumors not belonging to the SMT-SL spectrum, such as basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) or melanocytic tumors (melanomas and nevi). These skin and deep tumors (visceral tumors) not belonging to the Lynch spectrum of patients with proven SL have rarely been systematically studied for a dMMR phenotype.
French societies (INCa, Société Française de Gastroentérologie) have proposed the management of any patient with a mutation in one of the MMR system genes. Compliance with follow-up is a major public health issue. Digestive follow-up (regular colonoscopies) is only 68%, whereas gynecological follow-up is only 73% to 80%. Other types of follow-up, notably dermatological, have rarely been analyzed, and above all we have no data on compliance in France.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with Lynch syndrome undergoing screening for Muir-Torre syndrome | Other |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sampling of suspected skin lesions (in accordance with good care practices). | Diagnostic Test | Sampling of suspected skin lesions (in accordance with good care practices) and swabbing of skin microbiota. |
| Measure | Description | Time Frame |
|---|---|---|
| Prevalence of Muir-Torre syndrome (MTS) in the population of patients with Lynch syndrome | Proportion of patients with Muir-Torre Syndrome confirmed by the occurrence of a sebaceous tumor (sebaceous adenoma, sebaceoma, sebaceous carcinoma) or several keratoacanthomas among patients with Lynch Syndrome. These tumors may or may not have had the mismatch repair system analyzed by immunohistochemistry (analysis of the 4 antibodies MLH1, PMS2, MSH2, MSH6) or by molecular biology (search for microsatellite instability). If the mismatch repair system has been studied, it must be deficient and the proteins absent on immunohistochemistry must be consistent with the mutated gene in Lynch Syndrome. If a block or slides are still available, sebaceous skin tumors or keratoacanthomas will be re-evaluated at Nîmes University Hospital for confirmation of the diagnosis. | Up to 6 months after inclusion |
| Measure | Description | Time Frame |
|---|---|---|
| Dermatological clinical manifestations in patients with confirmed Lynch Syndrome | Presence of clinical dermatological signs associated with Lynch syndrome. YES/NO | Up to 6 months after inclusion |
| Non-sebaceous skin lesions and Deep-seated tumors not belonging to the narrow spectrum of Lynch syndrome. Presence of antibody MLH1 |
| Measure | Description | Time Frame |
|---|---|---|
| Constitution of a biobank | Collection of previously excised cutaneous and deep tumour lesions kept in a public or private pathological anatomy facility for these patients | Up to 6 months after inclusion |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Eric FROUIN, Dr. | Contact | +334 66 68 82 74 | Eric.frouin@chu-nimes.fr | |
| Anissa MEZGARI | Contact | +44466684236 | drc@chu-nimes.fr |
| Name | Affiliation | Role |
|---|---|---|
| Pierre STOEBNER, Prof. | Nîmes University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU de Nîmes | Recruiting | Nîmes | Gard | 30029 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36773823 | Background | Zhong CS, Horiguchi M, Uno H, Ukaegbu C, Chittenden A, LeBoeuf NR, Syngal S, Nambudiri VE, Yurgelun MB. Clinical factors associated with skin neoplasms in individuals with Lynch syndrome in a longitudinal observational cohort. J Am Acad Dermatol. 2023 Jun;88(6):1282-1290. doi: 10.1016/j.jaad.2023.01.035. Epub 2023 Feb 9. | |
| 18270343 |
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Sampling of suspected skin lesions (in accordance with good care practice) and swabbing of skin microbiota.
Collection of previously excised cutaneous and deep tumour lesions kept in a public or private pathological anatomy facility for these patients.
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| Constitution of a biobank | Genetic | Collection of previously excised cutaneous and deep tumour lesions kept in a public or private pathological anatomy facility for these patients |
|
Molecular analysis (MSI test) and immunohistochemical analysis. Presence of antibody MLH1 on other tumour tissues (YES/NO) to determine the mismatch repair deficient (or MSI = pathological) or proficient (or MSS = normal) status of these lesions (and thereby their link with Muir-Torre syndrome). |
| Up to 6 months after inclusion |
| Non-sebaceous skin lesions and Deep-seated tumors not belonging to the narrow spectrum of Lynch syndrome. Presence of antibody PMS2 | Molecular analysis (MSI test) and immunohistochemical analysis. Presence of antibody PMS2 on other tumour tissues (YES/NO) to determine the mismatch repair deficient (or MSI = pathological) or proficient (or MSS = normal) status of these lesions (and thereby their link with Muir-Torre syndrome). | Up to 6 months after inclusion |
| Non-sebaceous skin lesions and Deep-seated tumors not belonging to the narrow spectrum of Lynch syndrome. Presence of antibody MSH2 | Molecular analysis (MSI test) and immunohistochemical analysis. Presence of antibody MSH2 on other tumour tissues (YES/NO) to determine the mismatch repair deficient (or MSI = pathological) or proficient (or MSS = normal) status of these lesions (and thereby their link with Muir-Torre syndrome). | Up to 6 months after inclusion |
| Non-sebaceous skin lesions and Deep-seated tumors not belonging to the narrow spectrum of Lynch syndrome. Presence of antibody MSH6 | Molecular analysis (MSI test) and immunohistochemical analysis. Presence of antibody MSH6 (YES/NO) on other tumour tissues, to determine the mismatch repair deficient (or MSI = pathological) or proficient (or MSS = normal) status of these lesions (and thereby their link with Muir-Torre syndrome). | Up to 6 months after inclusion |
| South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008 Feb 20;100(4):277-81. doi: 10.1093/jnci/djm291. Epub 2008 Feb 12. |
| 29542113 | Background | Adan F, Crijns MB, Zandstra WSE, Bekkenk MW, Bleeker FE, Dekker E, van Leerdam ME. Cumulative risk of skin tumours in patients with Lynch syndrome. Br J Dermatol. 2018 Aug;179(2):522-523. doi: 10.1111/bjd.16552. Epub 2018 May 29. No abstract available. |
| 36418753 | Background | Aziz S, O'Sullivan H, Heelan K, Alam A, McVeigh TP. Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review. Fam Cancer. 2023 Apr;22(2):167-175. doi: 10.1007/s10689-022-00319-8. Epub 2022 Nov 23. |
| 30376427 | Background | Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Middha S, Hechtman J, Zehir A, Dubard-Gault M, Tran C, Stewart C, Sheehan M, Penson A, DeLair D, Yaeger R, Vijai J, Mukherjee S, Galle J, Dickson MA, Janjigian Y, O'Reilly EM, Segal N, Saltz LB, Reidy-Lagunes D, Varghese AM, Bajorin D, Carlo MI, Cadoo K, Walsh MF, Weiser M, Aguilar JG, Klimstra DS, Diaz LA Jr, Baselga J, Zhang L, Ladanyi M, Hyman DM, Solit DB, Robson ME, Taylor BS, Offit K, Berger MF, Stadler ZK. Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol. 2019 Feb 1;37(4):286-295. doi: 10.1200/JCO.18.00283. Epub 2018 Oct 30. |
| 37301271 | Background | Poumeaud F, Valentin T, Vande Perre P, Jaffrelot M, Bonnet D, Chibon F, Chevreau C, Selves J, Guimbaud R, Fares N. Special features of sarcomas developed in patients with Lynch syndrome: A systematic review. Crit Rev Oncol Hematol. 2023 Aug;188:104055. doi: 10.1016/j.critrevonc.2023.104055. Epub 2023 Jun 8. |
| ID | Term |
|---|---|
| D002280 | Carcinoma, Basal Cell |
| D002294 | Carcinoma, Squamous Cell |
| D003123 | Colorectal Neoplasms, Hereditary Nonpolyposis |
| D055653 | Muir-Torre Syndrome |
| D002277 | Carcinoma |
| D012878 | Skin Neoplasms |
| ID | Term |
|---|---|
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D018295 | Neoplasms, Basal Cell |
| D018307 | Neoplasms, Squamous Cell |
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009386 | Neoplastic Syndromes, Hereditary |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D049914 | DNA Repair-Deficiency Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D012626 | Sebaceous Gland Neoplasms |
| D055847 | Lynch Syndrome II |
| D012625 | Sebaceous Gland Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012873 | Skin Diseases, Genetic |
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