Mar Giner-Calabuig1,2, Seila De Leon1, Julian Wang1, Tara D Fehlmann3, Chinedu Ukaegbu3, Joanna Gibson4, Miren Alustiza-Fernandez2, Maria-Dolores Pico2, Cristina Alenda2, Maite Herraiz5, Marta Carrillo-Palau6, Inmaculada Salces7, Josep Reyes8, Silvia P Ortega8, Antònia Obrador-Hevia9, Michael Cecchini1, Sapna Syngal3, Elena Stoffel10, Nathan A Ellis11, Joann Sweasy12, Rodrigo Jover2, Xavier Llor1, Rosa M Xicola13. 1. Department of Medicine and Cancer Center, Yale University School of Medicine, New Haven, CT, USA. 2. Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain. 3. Divisions of Cancer Genetics and Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 4. Department of Pathology and Cancer Center, Yale University School of Medicine, New Haven, CT, USA. 5. Departamento de Digestivo, Clínica Universidad de Navarra, Navarra, Spain. 6. Servicio de Medicina Digestiva, Hospital Universitario de Canarias, Tenerife, Spain. 7. Servicio de Medicina Digestiva, Hospital 12 de Octubre, Madrid, Spain. 8. Servei de Digestiu, Hospital Comarcal d'Inca, Mallorca, Spain. 9. Hospital Universitari Son Espases, Mallorca, Spain. 10. Division of Gastroenterology and Hepatology, Department of Internal Medicine, and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. 11. Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. 12. Department of Therapeutic Radiobiology and Cancer Center, Yale University, New Haven, CT, USA. 13. Department of Medicine and Cancer Center, Yale University School of Medicine, New Haven, CT, USA. rosa.xicola@yale.edu.
Abstract
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
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Authors: Rosa M Xicola; Xavier Llor; Elisenda Pons; Antoni Castells; Cristina Alenda; Virgínia Piñol; Montserrat Andreu; Sergi Castellví-Bel; Artemio Payá; Rodrigo Jover; Xavier Bessa; Anna Girós; José M Duque; David Nicolás-Pérez; Ana M Garcia; Joaquin Rigau; Miquel A Gassull Journal: J Natl Cancer Inst Date: 2007-02-07 Impact factor: 13.506
Authors: María Rodríguez-Soler; Lucía Pérez-Carbonell; Carla Guarinos; Pedro Zapater; Adela Castillejo; Victor M Barberá; Miriam Juárez; Xavier Bessa; Rosa M Xicola; Juan Clofent; Luis Bujanda; Francesc Balaguer; Josep-Maria Reñé; Luisa de-Castro; José C Marín-Gabriel; Angel Lanas; Joaquín Cubiella; David Nicolás-Pérez; Alejandro Brea-Fernández; Sergi Castellví-Bel; Cristina Alenda; Clara Ruiz-Ponte; Angel Carracedo; Antoni Castells; Montserrat Andreu; Xavier Llor; José L Soto; Artemio Payá; Rodrigo Jover Journal: Gastroenterology Date: 2013-01-24 Impact factor: 22.682