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Genetics and Genomics

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

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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.

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Fig. 1: De novo mutational signature profile of MMR-deficient tumours.
Fig. 2: Mutational signature exposure by cluster.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available yet but will be following NCI data-sharing policies. However, datasets could be available from the corresponding author on reasonable request.

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Acknowledgements

The results shown here are in part based on data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Funding

This work was supported by grants from the National Cancer Institute (1K01CA204431-01A1 RMX), the Prevent Cancer Foundation (RMX), Colorectal Cancer Alliance’s Chris4Life grant (RMX), pre-doctoral grant from Conselleria d’Educació de la Generalitat Valenciana. VALi+d. EXP ACIF/2010/018, ACIF/2016/002 (MGC), Instituto de Salud Carlos III PI17/01756 (RJ), Asociación Española de Gastroenterología. Beca Tamarite 2017 (RJ) and the Donaldson Foundation (SS and CU).

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Authors and Affiliations

  1. Department of Medicine and Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    Mar Giner-Calabuig, Seila De Leon, Julian Wang, Michael Cecchini, Xavier Llor & Rosa M. Xicola

  2. Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain

    Mar Giner-Calabuig, Miren Alustiza-Fernandez, Maria-Dolores Pico, Cristina Alenda & Rodrigo Jover

  3. Divisions of Cancer Genetics and Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Tara D. Fehlmann, Chinedu Ukaegbu & Sapna Syngal

  4. Department of Pathology and Cancer Center, Yale University School of Medicine, New Haven, CT, USA

    Joanna Gibson

  5. Departamento de Digestivo, Clínica Universidad de Navarra, Navarra, Spain

    Maite Herraiz

  6. Servicio de Medicina Digestiva, Hospital Universitario de Canarias, Tenerife, Spain

    Marta Carrillo-Palau

  7. Servicio de Medicina Digestiva, Hospital 12 de Octubre, Madrid, Spain

    Inmaculada Salces

  8. Servei de Digestiu, Hospital Comarcal d’Inca, Mallorca, Spain

    Josep Reyes & Silvia P. Ortega

  9. Hospital Universitari Son Espases, Mallorca, Spain

    Antònia Obrador-Hevia

  10. Division of Gastroenterology and Hepatology, Department of Internal Medicine, and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    Elena Stoffel

  11. Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Nathan A. Ellis

  12. Department of Therapeutic Radiobiology and Cancer Center, Yale University, New Haven, CT, USA

    Joann Sweasy

Authors
  1. Mar Giner-Calabuig
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  2. Seila De Leon
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  21. Rodrigo Jover
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  22. Xavier Llor
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  23. Rosa M. Xicola
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Contributions

Conceptualisation (MGC, XL, RMX); Data curation (MGC, SDL, JW, MDP, TF, CU, MH, MCP, IS); Formal analysis (MGC, RMX); Funding acquisition (RJ, JS, XL, RMX); Investigation (MGC, SDL, JW, JG, CA); Project administration (RMX); Resources (TF, CU, SS, MH, MCP, IS, EMS, NAE, JS, MA, MDP, RJ, JR, SPO, AOH); Supervision (RMX); Validation (MGC, SDL); Visualisation (MGC, JW, RMX); Writing—original draft (MGC, XL, RMX); Writing—review and editing (MGC, CU, SS, ES, JG, MC, RJ, NAE, XL, RMX).

Corresponding author

Correspondence to Rosa M. Xicola.

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Competing interests

SS is a consultant for Myriad Genetics and DC Health Technologies and has rights to an inventor portion of the licensing revenue from PREMM5. The remaining authors declare no competing interests.

Ethics approval and consent to participate

Patients were recruited and consented in their original institutions under projects approved by institutional human research review committees. At Yale University the project was approved by the Biomedical Institutional Review Board. All data were shared in a de-identified manner to unlink any patient’s personal identifiers from their samples. The study was performed in accordance with the Declaration of Helsinki.

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Giner-Calabuig, M., De Leon, S., Wang, J. et al. Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential. Br J Cancer 126, 1595–1603 (2022). https://doi.org/10.1038/s41416-022-01754-1

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