title: Prevalence of germline MUTYH mutations among Lynch-like syndrome patients.
abstract: OBJECTIVE
  Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients.
  
  
  METHODS
  Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed.
  
  
  RESULTS
  We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001).
  
  
  CONCLUSIONS
  A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain.
authors: Adela
authors: A
authors: Castillejo
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Gardenia
authors: G
authors: Vargas
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain.
authors: María Isabel
authors: MI
authors: Castillejo
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Matilde
authors: M
authors: Navarro
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain.
authors: Víctor Manuel
authors: VM
authors: Barberá
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Sara
authors: S
authors: González
authors: Laboratory of Investigation, Alicante University Hospital, Alicante, Spain.
authors: Eva
authors: E
authors: Hernández-Illán
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IdIBGI, Girona, Spain.
authors: Joan
authors: J
authors: Brunet
authors: Medical Oncology Service, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors: Teresa
authors: T
authors: Ramón y Cajal
authors: University Hospital of Vall d'Hebron, Barcelona, Spain.
authors: Judith
authors: J
authors: Balmaña
authors: Genetics Department, La Fe University Hospital, Valencia, Spain.
authors: Silvestre
authors: S
authors: Oltra
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Sílvia
authors: S
authors: Iglesias
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IdIBGI, Girona, Spain.
authors: Angela
authors: A
authors: Velasco
authors: Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
authors: Ares
authors: A
authors: Solanes
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Olga
authors: O
authors: Campos
authors: Genetic Counselling in Cancer, Hereditary Cancer Program, Elche University Hospital, Elche, Alicante, Spain; Department of Medical Oncology, Elche University Hospital, Elche, Alicante, Spain.
authors: Ana Beatriz
authors: AB
authors: Sánchez Heras
authors: Department of Medical Oncology, Elche University Hospital, Elche, Alicante, Spain.
authors: Javier
authors: J
authors: Gallego
authors: Vall d́Hebron Institute of Oncology, Barcelona, Spain.
authors: Estela
authors: E
authors: Carrasco
authors: Medical Oncology Service, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
authors: Dolors
authors: D
authors: González Juan
authors: Genetic Counselling in Cancer, Hereditary Cancer Program, La Fe University Hospital, Valencia, Spain.
authors: Angel
authors: A
authors: Segura
authors: Genetic Counselling in Cancer, Hereditary Cancer Program, Clinical University Hospital of Valencia, Valencia, Spain.
authors: Isabel
authors: I
authors: Chirivella
authors: Genetic Counselling in Cancer, Hereditary Cancer Program, Valencian Institute of Oncology, Valencia, Spain.
authors: María José
authors: MJ
authors: Juan
authors: Genetic Counselling in Cancer, Hereditary Cancer Program, Provincial Hospital of Castellón, Castellón, Spain.
authors: Isabel
authors: I
authors: Tena
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Conxi
authors: C
authors: Lázaro
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
authors: Ignacio
authors: I
authors: Blanco
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Marta
authors: M
authors: Pineda
authors: Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors: Gabriel
authors: G
authors: Capellá
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain. Electronic address: soto_jos@gva.es.
authors: José Luis
authors: JL
authors: Soto
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: KRAS mutations; Lynch syndrome; MAP syndrome; MUTYH