Detalle Publicación


Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential

Autores: Giner-Calabuig, M.; De León, S.; Wang, J. L.; Fehlmann, T. D.; Ukaegbu, C.; Gibson, J.; Alustiza-Fernández, M.; Pico, M. D.; Alenda, C.; Herráiz Bayod, Maite; Carrillo-Palau, M.; Salces, I.; Reyes, J.; Ortega, S. P.; Obrador-Hevia, A.; Cecchini, M.; Syngal, S.; Stoffel, E.; Ellis, N. A.; Sweasy, J.; Jover, R.; Llor, X.; Xicola, R. M. (Autor de correspondencia)
Título de la revista: BRITISH JOURNAL OF CANCER
ISSN: 0007-0920
Volumen: 126
Número: 11
Páginas: 1595 - 1603
Fecha de publicación: 2022
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.