Adela Castillejo1, Eva Hernández-Illán2, María Rodriguez-Soler3, Lucía Pérez-Carbonell2, Cecilia Egoavil4, Victor M Barberá1, María-Isabel Castillejo1, Carla Guarinos2, Eduardo Martínez-de-Dueñas5, María-Jose Juan6, Ana-Beatriz Sánchez-Heras7, Zaida García-Casado8, Clara Ruiz-Ponte9, Alejandro Brea-Fernández9, Miriam Juárez2, Luis Bujanda10, Juan Clofent11, Xavier Llor12, Montserrat Andreu13, Antoni Castells14, Angel Carracedo9, Cristina Alenda4, Artemio Payá4, Rodrigo Jover15, José-Luis Soto1. 1. Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain. 2. Research Laboratory, Alicante University Hospital, Alicante, Spain. 3. Research Laboratory, Alicante University Hospital, Alicante, Spain Department of Gastroenterology, Alicante University Hospital, Alicante, Spain. 4. Department of Pathology, Alicante University Hospital, Alicante, Spain. 5. Medical Oncology Department, Consorcio Provincial Hospital, Castellon, Spain. 6. Hereditary Cancer Unit, Valencian Institute of Oncology, Valencia, Spain. 7. Genetic Counseling in Cancer Unit, Elche University Hospital, Elche, Spain. 8. Laboratory of Molecular Biology, Valencian Institute of Oncology, Valencia, Spain. 9. Galician 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. Department of Gastroenterology, Donostia Hospital-Instituto Biodonostia, CIBERehd, University of the Basque Country (UPV/EHU), San Sebastian, Spain. 11. Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, Sagunto, Spain. 12. Section of Digestive Diseases and Nutrition, Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA. 13. Department of Gastroenterology, IMIM, Hospital del Mar, Parc de Salut Mar. Pompeu Fabra University, Barcelona, Spain. 14. Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain. 15. Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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