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

• Published in: British journal of cancer Vol. 126; no. 11; pp. 1595 - 1603
• Main Authors: Giner-Calabuig, Mar, De Leon, Seila, Wang, Julian, Fehlmann, Tara D., Ukaegbu, Chinedu, Gibson, Joanna, Alustiza-Fernandez, Miren, Pico, Maria-Dolores, Alenda, Cristina, Herraiz, Maite, Carrillo-Palau, Marta, Salces, Inmaculada, Reyes, Josep, Ortega, Silvia P., Obrador-Hevia, Antònia, Cecchini, Michael, Syngal, Sapna, Stoffel, Elena, Ellis, Nathan A., Sweasy, Joann, Jover, Rodrigo, Llor, Xavier, Xicola, Rosa M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2022; Nature Publishing Group
• Subjects: 631/67/1504/1885/1393; 692/4028/67/69; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms; Cancer Research; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Mismatch Repair - genetics; Drug Resistance; Epidemiology; Genetic disorders; Histocompatibility antigen HLA; Humans; Immunogenicity; Microsatellite Instability; Mismatch repair; Mismatch Repair Endonuclease PMS2 - genetics; MLH1 protein; Molecular Medicine; MSH2 protein; MSH6 protein; Mutation; MutL Protein Homolog 1 - genetics; Neoantigens; Neoplastic Syndromes, Hereditary; Next-generation sequencing; Oncology; Phenotypes; Pms2 protein; Precision medicine; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-022-01754-1

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.