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

Abstract

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.

Fig. 1. De novo mutational signature profile of MMR-deficient tumours.

Clustering representation of de novo extracted signatures to each tumour based on the similarity of these with COSMIC signatures. Each row represents one tumour and each column one signature. Annotation describes phenotype, loss of MMR protein complex expression, MANTIS classification. LLS Lynch-like syndrome, LS Lynch syndrome, MSI.BRAF Microsatellite unstable with BRAF V600E, g-MSS global microsatellite stable MANTIS < 0.4, g-MSI global microsatellite unstable MANTIS > 0.4, MMR.D loss of MMR protein expression, MutL loss of expression of MLH1 and/or PMS2, MutS loss of expression of MSH2 and/or MSH6.

Fig. 2. Mutational signature exposure by cluster.

Representation of the distribution of signature exposure for each tumour by cluster. The black line represents the median. FDR false discovery rate.