Ortega, S. P. (Silvia P.)

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    Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential
    (Springer, 2022) Giner-Calabuig, M. (Mar); De-León, S. (Seila); Wang, J. (Julián); Fehlmann, T. D. (Tara D.); Ukaegbu, Ch. (Chinedu); Gibson, J. (Joanna); Alustiza, M. (Miren); Picó, M.D. (María Dolores); Alenda, C. (Cristina); Herraiz, M. T. (María Teresa); Carrillo-Palau, M. (Marta); Salces, I. (Inmaculada); Reyes, J. (Josep); Ortega, S. P. (Silvia P.); Obrador-Hevia, A. (Antònia); Cecchini, M. (Michele); Syngal, S. (Sapna); Stoffel, E. (Elena); Nathan, E. (Ellis); Sweasy, J. (Joann); Jover, R. (Rodrigo); Llor, X. (Xavier); Xicola, R.M. (Rosa M.)
    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.