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

Giner-Calabuig, M.; De Leon, S.; Wang, J.; Fehlmann, T.; Ukaegbu, C.; Gibson, J.; Alustiza Fernandez, M.; Pico, M.-D.; Alenda, C.; Herraiz, M.; Carrillo-Palau, M.; Salces, I.; Reyes, J.; Ortega, S. P.; Obrador, A.; Cecchini, M.; Syngal, S.; Stoffel, E.; Ellis, N. A.; Sweasy, J.; Jover, R.; Llor, X.; Xicola, R. M.

doi:10.1101/2021.09.28.460630

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bioRxiv · 10.1101/2021.09.28.460630

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

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Abstract

BackgroundMismatch repair (MMR) deficiency is the hallmark of tumors 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 characterization to identify novel features that can impact tumor behavior and clinical management. MethodsWe tested 105 MMR-deficient colorectal cancer tumors (25 LS, 35 LLS, and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. Results78% of tumors showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumors. 22% of tumors showed weaker features of MMR deficiency, 73% lost MSH2/MSH6 expression and included half of LS and LLS tumors. Remarkably, 9% of all tumors lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumors that show the strongest contribution of MMR-deficient tumors. ConclusionsNext-generation sequencing approaches allow for a granular molecular characterization of MMR-deficient tumors, which can be essential to properly diagnose and treat patients with these tumors in the setting of personalized medicine.

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Giner-Calabuig, M., De Leon, S., Wang, J., Fehlmann, T., Ukaegbu, C., Gibson, J., Alustiza Fernandez, M., Pico, M.-D., Alenda, C., Herraiz, M., Carrillo-Palau, M., Salces, I., Reyes, J., Ortega, S. P., Obrador, A., Cecchini, M., Syngal, S., Stoffel, E., Ellis, N. A., Sweasy, J., Jover, R., Llor, X., Xicola, R. M.. 2021-09-29. Mutational signature profiling classifies subtypes of clinically different mismatch repair deficient tumors with a differential immunogenic response potential. https://doi.org/10.1101/2021.09.28.460630

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