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High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers
  1. Maribel González-Acosta1,
  2. Fátima Marín1,
  3. Benjamin Puliafito1,
  4. Nuria Bonifaci1,
  5. Anna Fernández1,
  6. Matilde Navarro1,
  7. Hector Salvador2,
  8. Francesc Balaguer3,
  9. Silvia Iglesias1,
  10. Angela Velasco4,
  11. Elia Grau Garces1,
  12. Victor Moreno5,6,
  13. Luis Ignacio Gonzalez-Granado7,
  14. Pilar Guerra-García8,
  15. Rosa Ayala9,
  16. Benoît Florkin10,
  17. Christian Kratz11,
  18. Tim Ripperger12,
  19. Thorsten Rosenbaum13,
  20. Danuta Januszkiewicz-Lewandowska14,
  21. Amedeo A Azizi15,
  22. Iman Ragab16,
  23. Michaela Nathrath17,18,
  24. Hans-Jürgen Pander19,
  25. Stephan Lobitz20,
  26. Manon Suerink21,
  27. Karin Dahan22,
  28. Thomas Imschweiler23,
  29. Ugur Demirsoy24,
  30. Joan Brunet1,4,
  31. Conxi Lázaro1,
  32. Daniel Rueda25,
  33. Katharina Wimmer26,
  34. Gabriel Capellá1,
  35. Marta Pineda1
  1. 1 Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Hereditary Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Institut d’Investigació Biomèdica de Bellvitge – IDIBELL, Ciber Oncología (CIBERONC) - Instituto de Salud Carlos III, L'Hospitalet de Llobregat, Barcelona, Spain
  2. 2 Pediatric Oncology Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
  3. 3 Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  4. 4 Hereditary Cancer Program, Catalan Institute of Oncology - ICO, Institut d’Investigació Biomèdica de Girona - IDIBGI, Girona, Spain
  5. 5 Cancer Prevention and Control Program, Catalan Institute of Oncology - ICO, Institut d’Investigació Biomèdica de Bellvitge – IDIBELL, CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
  6. 6 Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
  7. 7 Immunodeficiencies Unit, Department of Pediatrics, Doce de Octubre University Hospital, i+12 Research Institute; Complutense University of Madrid, Madrid, Spain
  8. 8 Hematology and Oncology Unit, Department of Pediatrics, Doce de Octubre University Hospital, Madrid, Spain
  9. 9 Department of Hematology, Doce de Octubre University Hospital, i+12 Research Institute, Madrid, Spain
  10. 10 University Department of Pediatrics, CHR Citadelle, Liege, Belgium
  11. 11 Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
  12. 12 Department of Human Genetics, Hannover Medical School, Hannover, Germany
  13. 13 Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
  14. 14 Department of Pediatric Oncology, Hematology and Transplantation, Poznań University of Medical Sciences, Poznań, Poland
  15. 15 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  16. 16 Pediatrics Department, Hematology-Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
  17. 17 Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany
  18. 18 Pediatric Oncology Center, Department of Pediatrics, Technische Universität München, Munchen, Germany
  19. 19 Institut für Klinische Genetik, Olgahospital, Stuttgart, Germany
  20. 20 Department of Pediatric Oncology/Pediatric Hematology, Kliniken der Stadt Köln gGmbH, Children’s Hospital Amsterdamer Strasse, Koln, Germany
  21. 21 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  22. 22 Centre de Génétique Humaine, Institut de Pathologie et de Génétique (IPG), Gosselies, Belgium
  23. 23 Pediatric Oncology, Helios-Klinikum, Krefeld, Germany
  24. 24 Department of Pediatric Oncology, Kocaeli Universitesi, Kocaeli, Turkey
  25. 25 Hereditary Cancer Laboratory, Doce de Octubre University Hospital, i+12 Research Institute, Madrid, Spain
  26. 26 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
  1. Correspondence to Dr Gabriel Capellá, Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat 08908, Catalunya, Spain; gcapella{at}; Dr Marta Pineda, Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat 08908, Catalunya, Spain; mpineda{at}


Introduction Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.

Materials and methods Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.

Results The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).

Conclusions The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

  • lynch syndrome
  • constitutional mismatch repair deficiency
  • microsatellite instability
  • next generation sequencing
  • highly sensitive methodologies

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  • GC and MP are joint senior authors.

  • MG-A, FM and BP are joint first authors.

  • GC and MP contributed equally.

  • MG-A, FM and BP contributed equally.

  • Contributors MG-A, FM and BP designed and performed the research, analysed the data and wrote the manuscript. NB assisted in bioinformatics analyses. AF assisted in molecular analyses. MaN, HS, FB, SI, AV, EGG, VM, LIG-G, PG-G, BF, CK, TiR, ThR, DJ-L, AAA, IR, MiN, H-JP, SL, MS, KD, TI, UD and JB provided samples and clinical data. VM also contributed to the statistical analysis. RA assisted in molecular analyses. CL, DR and KW provided samples, supervised the study and wrote the manuscript. MP and GC conceived the project, supervised the study, analysed the data and wrote the manuscript. All authors revised and approved the manuscript. MP and GC shared the last authorship.

  • Funding This work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds - a way to build Europe (grant SAF2015-68016-R), CIBERONC and the Government of Catalonia (grants 2017SGR1282 and PERIS SLT002/16/0037), and the AECC fellowship to MG-A. AF was supported by a grant from the Catalonian Health Department (SLT002/16/00409). FM was supported by CIBERONC. We thank the CERCA Programme for institutional support.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the ethics committee of the Bellvitge University Hospital (HUB) (file no PR255/15). Written informed consent was obtained from all individuals.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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