title: Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.
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.
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: Adela
authors.identifier: http://orcid.org/0000-0002-9581-6285
authors.initials: A
authors.lastname: Castillejo
authors.affiliation: Research Laboratory, Alicante University Hospital, Alicante, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernández-Illán
authors.affiliation: Research Laboratory, Alicante University Hospital, Alicante, Spain Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rodriguez-Soler
authors.affiliation: Research Laboratory, Alicante University Hospital, Alicante, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Pérez-Carbonell
authors.affiliation: Department of Pathology, Alicante University Hospital, Alicante, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Egoavil
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Barberá
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: María-Isabel
authors.initials: MI
authors.lastname: Castillejo
authors.affiliation: Research Laboratory, Alicante University Hospital, Alicante, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarinos
authors.affiliation: Medical Oncology Department, Consorcio Provincial Hospital, Castellon, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez-de-Dueñas
authors.affiliation: Hereditary Cancer Unit, Valencian Institute of Oncology, Valencia, Spain.
authors.forename: María-Jose
authors.initials: MJ
authors.lastname: Juan
authors.affiliation: Genetic Counseling in Cancer Unit, Elche University Hospital, Elche, Spain.
authors.forename: Ana-Beatriz
authors.initials: AB
authors.lastname: Sánchez-Heras
authors.affiliation: Laboratory of Molecular Biology, Valencian Institute of Oncology, Valencia, Spain.
authors.forename: Zaida
authors.initials: Z
authors.lastname: García-Casado
authors.affiliation: 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.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Brea-Fernández
authors.affiliation: Research Laboratory, Alicante University Hospital, Alicante, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Juárez
authors.affiliation: Department of Gastroenterology, Donostia Hospital-Instituto Biodonostia, CIBERehd, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, Sagunto, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Clofent
authors.affiliation: Section of Digestive Diseases and Nutrition, Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.affiliation: Department of Gastroenterology, IMIM, Hospital del Mar, Parc de Salut Mar. Pompeu Fabra University, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.affiliation: Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: 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.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Department of Pathology, Alicante University Hospital, Alicante, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.affiliation: Department of Pathology, Alicante University Hospital, Alicante, Spain.
authors.forename: Artemio
authors.initials: A
authors.lastname: Payá
authors.affiliation: Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Soto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005820:Genetic Testing / Q000592:standards; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1
keywords: Cancer: colon; Clinical genetics; Epigenetics