Sahra Bodo1, Chrystelle Colas2, Olivier Buhard1, Ada Collura1, Julie Tinat3, Noémie Lavoine4, Agathe Guilloux1, Alexandra Chalastanis1, Philippe Lafitte1, Florence Coulet5, Marie-Pierre Buisine6, Denisa Ilencikova7, Clara Ruiz-Ponte8, Miriam Kinzel9, Sophie Grandjouan10, Hilde Brems11, Sophie Lejeune12, Hélène Blanché13, Qing Wang14, Olivier Caron15, Odile Cabaret16, Magali Svrcek17, Dominique Vidaud18, Béatrice Parfait18, Alain Verloes19, Ulrich J Knappe20, Florent Soubrier21, Isabelle Mortemousque22, Alexander Leis23, Jessie Auclair-Perrossier14, Thierry Frébourg3, Jean-François Fléjou17, Natacha Entz-Werle24, Julie Leclerc6, David Malka25, Odile Cohen-Haguenauer26, Yael Goldberg27, Anne-Marie Gerdes28, Faten Fedhila29, Michèle Mathieu-Dramard30, Richard Hamelin1, Badre Wafaa31, Marion Gauthier-Villars32, Franck Bourdeaut33, Eamonn Sheridan34, Hans Vasen35, Laurence Brugières4, Katharina Wimmer36, Martine Muleris37, Alex Duval38. 1. INSERM, UMR_S 938 Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, équipe labellisée par la Ligue Nationle contre le Cancer, Paris, France; UPMC Univ Paris, Paris, France. 2. INSERM, UMR_S 938 Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, équipe labellisée par la Ligue Nationle contre le Cancer, Paris, France; UPMC Univ Paris, Paris, France; AP-HP, Laboratoire d'Oncogénétique et d'Angiogénétique, GH Pitié-Salpétrière, Paris, France. 3. Département de génétique, Hôpital universitaire, Rouen, France. 4. Department of Children and Adolescents Oncology, Gustave Roussy Cancer Institute, Villejuif, France. 5. UPMC Univ Paris, Paris, France; AP-HP, Laboratoire d'Oncogénétique et d'Angiogénétique, GH Pitié-Salpétrière, Paris, France. 6. Institut de Biochimie et Biologie moléculaire, Oncologie et Génétique Moléculaires, CHRU Lille, Lille, France; INSERM UMR837 et Université Lille, Lille, France. 7. 2nd Pediatric Department, Children's University Hospital, Comenius University, Bratislava, Slovakia. 8. Fundación Pública Galega de Medicina Xenómica (FPGMX) SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Santiago de Compostela, Spain. 9. Praxis für Medizinische Genetik, Berlin, Germany. 10. CHU Cochin, faculté René Descartes Paris-V, Paris, France. 11. Department of Human Genetics, KU Leuven, Leuven, Belgium. 12. CHRU Lille, Service de génétique clinique, Lille, France. 13. CEPH, Fondation Jean Dausset, Institut de Génétique Moléculaire, Paris, France. 14. Plateforme de Génétique constitutionnelle HCL-CLB, Laboratoire de recherche translationnelle, Centre Léon Bérard, Lyon, France. 15. Department of Medical Oncology, Gustave Roussy Cancer Institute, Villejuif, France. 16. Service de Génétique, Département de Biologie et Pathologie Médicales, Institut Gustave Roussy, Villejuif, France. 17. INSERM, UMR_S 938 Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, équipe labellisée par la Ligue Nationle contre le Cancer, Paris, France; UPMC Univ Paris, Paris, France; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. 18. INSERM UMR745 Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France. 19. AP-HP, Département de Génétique and INSERM UMR 1141 PROTECT, Hôpital Robert Debré, Paris, France. 20. Department of Neurosurgery, Johannes Wesling Klinikum, Minden, Germany. 21. AP-HP, Département de génétique, GH Pitié-Salpêtrière, Paris, France. 22. CHRU de Tours, Service de Génétique, Tours, France. 23. French Medical Institute for Children, Kabul, Afghanistan. 24. Pédiatrie Onco-Hématologie Pédiatrie CHRU Hautepierre UdS EA, Strasbourg, France. 25. Department of Cancer Medicine, Gustave Roussy, Villejuif, France. 26. Service d'Oncologie Médicale, Hôpital Saint-Louis, Paris, France. 27. Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 28. Department of Clinical Genetics, Copenhagen University Hospital Rigshospital, Copenhagen, Denmark. 29. Service de médecine infantile, hôpital d'enfants de Tunis, Tunis, Tunisia. 30. Unit of medical Genetics, Amiens University Hospital, Amiens, France. 31. Department of Hepato-Gastro-Enterology, Ibn Rochd, Hospital University Center, Casablanca, Morocco. 32. Service de Génétique, Institut Curie, Paris, France. 33. Department of Pediatric Oncology and INSERM U830, Institut Curie, Paris, France. 34. Department of Molecular Medicine, University of Leeds, Leeds, United Kingdom. 35. Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands. 36. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria. 37. INSERM, UMR_S 938 Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, équipe labellisée par la Ligue Nationle contre le Cancer, Paris, France; UPMC Univ Paris, Paris, France. Electronic address: martine.muleris@inserm.fr. 38. INSERM, UMR_S 938 Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, équipe labellisée par la Ligue Nationle contre le Cancer, Paris, France; UPMC Univ Paris, Paris, France. Electronic address: alex.duval@inserm.fr.
Abstract
BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.
BACKGROUND & AIMS:Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.
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Authors: Sofia Sagredou; Panagiotis Dalezis; Eirini Papadopoulou; Maria Voura; Maria V Deligiorgi; Michail Nikolaou; Mihalis I Panayiotidis; George Nasioulas; Vasiliki Sarli; Dimitrios T Trafalis Journal: Pharmaceutics Date: 2021-06-15 Impact factor: 6.321