Scientific publications

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

Jun 1, 2022 | Magazine: Bristish Journal of Cancer

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.

CITATION  Br J Cancer. 2022 Jun;126(11):1595-1603.
doi: 10.1038/s41416-022-01754-1. Epub 2022 Feb 23

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