Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential
Mar Giner-Calabuig 1 2 , Seila De Leon 1 , Julian Wang 1 , Tara D Fehlmann 3 , Chinedu Ukaegbu 3 , Joanna Gibson 4 , Miren Alustiza-Fernandez 2 , Maria-Dolores Pico 2 , Cristina Alenda 2 , Maite Herraiz 5 , Marta Carrillo-Palau 6 , Inmaculada Salces 7 , Josep Reyes 8 , Silvia P Ortega 8 , Antònia Obrador-Hevia 9 , Michael Cecchini 1 , Sapna Syngal 3 , Elena Stoffel 10 , Nathan A Ellis 11 , Joann Sweasy 12 , Rodrigo Jover 2 , Xavier Llor 1 , Rosa M Xicola 13
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.