title: POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance.
abstract: OBJECTIVE
  Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers.
  
  
  METHODS
  The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing.
  
  
  RESULTS
  Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors.
  
  
  CONCLUSIONS
  Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations.Genet Med 18 4, 325-332.
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bellido
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Aiza
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdés-Mas
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Tirso
authors.identifier: http://orcid.org/0000-0002-7616-7750
authors.initials: T
authors.lastname: Pons
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: González
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Darder
authors.affiliation: Gastroenterology Department, Hospital Dr. Josep Trueta, Girona, Spain.|Medical Science Department, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Piñol
authors.affiliation: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors.forename: José Luís
authors.identifier: http://orcid.org/0000-0003-0234-9188
authors.initials: JL
authors.lastname: Soto
authors.affiliation: Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.affiliation: Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO) and Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.|Medical Science Department, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000175:diagnosis / Q000235:genetics*; D000483:Alleles; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D004257:DNA Polymerase II / Q000737:chemistry / Q000235:genetics*; D004258:DNA Polymerase III / Q000737:chemistry / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000075223:Poly-ADP-Ribose Binding Proteins; D054730:Protein Interaction Domains and Motifs / Q000235:genetics
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human