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Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer
  1. Adela Castillejo1,
  2. Eva Hernández-Illán2,
  3. María Rodriguez-Soler2,3,
  4. Lucía Pérez-Carbonell2,
  5. Cecilia Egoavil4,
  6. Victor M Barberá1,
  7. María-Isabel Castillejo1,
  8. Carla Guarinos2,
  9. Eduardo Martínez-de-Dueñas5,
  10. María-Jose Juan6,
  11. Ana-Beatriz Sánchez-Heras7,
  12. Zaida García-Casado8,
  13. Clara Ruiz-Ponte9,
  14. Alejandro Brea-Fernández9,
  15. Miriam Juárez2,
  16. Luis Bujanda10,
  17. Juan Clofent11,
  18. Xavier Llor12,
  19. Montserrat Andreu13,
  20. Antoni Castells14,
  21. Angel Carracedo9,
  22. Cristina Alenda4,
  23. Artemio Payá4,
  24. Rodrigo Jover3,
  25. José-Luis Soto1
  1. 1Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain
  2. 2Research Laboratory, Alicante University Hospital, Alicante, Spain
  3. 3Department of Gastroenterology, Alicante University Hospital, Alicante, Spain
  4. 4Department of Pathology, Alicante University Hospital, Alicante, Spain
  5. 5Medical Oncology Department, Consorcio Provincial Hospital, Castellon, Spain
  6. 6Hereditary Cancer Unit, Valencian Institute of Oncology, Valencia, Spain
  7. 7Genetic Counseling in Cancer Unit, Elche University Hospital, Elche, Spain
  8. 8Laboratory of Molecular Biology, Valencian Institute of Oncology, Valencia, Spain
  9. 9Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clinico Santiago de Compostela, University of Santiago de Compostela Santiago de Compostela, Santiago de Compostela, Spain
  10. 10Department of Gastroenterology, Donostia Hospital-Instituto Biodonostia, CIBERehd, University of the Basque Country (UPV/EHU), San Sebastian, Spain
  11. 11Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, Sagunto, Spain
  12. 12Section of Digestive Diseases and Nutrition, Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA
  13. 13Department of Gastroenterology, IMIM, Hospital del Mar, Parc de Salut Mar. Pompeu Fabra University, Barcelona, Spain
  14. 14Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
  1. Correspondence to Dr José-Luis Soto, Molecular Genetics Laboratory, Elche University Hospital, Camino Almazara n° 11, Elche 03203, Spain; soto_jos{at}gva.es

Abstract

Background The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC).

Methods Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification.

Results Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004).

Conclusions Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.

  • Clinical genetics
  • Cancer: colon
  • Epigenetics

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