title: New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.
abstract: Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.
authors: Hereditary Cancer Program and lvalle@iconcologia.net.
authors: Laura
authors: L
authors: Valle
authors: Research Laboratory.
authors: Eva
authors: E
authors: Hernández-Illán
authors: Hereditary Cancer Program and.
authors: Fernando
authors: F
authors: Bellido
authors: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
authors: Gemma
authors: G
authors: Aiza
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors: Adela
authors: A
authors: Castillejo
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors: María-Isabel
authors: MI
authors: Castillejo
authors: Hereditary Cancer Program and.
authors: Matilde
authors: M
authors: Navarro
authors: Hereditary Cancer Program and.
authors: Nuria
authors: N
authors: Seguí
authors: Hereditary Cancer Program and.
authors: Gardenia
authors: G
authors: Vargas
authors: Research Laboratory.
authors: Carla
authors: C
authors: Guarinos
authors: Research Laboratory.
authors: Miriam
authors: M
authors: Juarez
authors: Department of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.
authors: Xavier
authors: X
authors: Sanjuán
authors: Hereditary Cancer Program and.
authors: Silvia
authors: S
authors: Iglesias
authors: Department of Pathology and.
authors: Cristina
authors: C
authors: Alenda
authors: Department of Pathology and.
authors: Cecilia
authors: C
authors: Egoavil
authors: Hereditary Cancer Unit, La Fe University Hospital, Valencia, Spain.
authors: Ángel
authors: Á
authors: Segura
authors: Hereditary Cancer Unit, Valencian Institute of Oncology, Valencia, Spain and.
authors: María-José
authors: MJ
authors: Juan
authors: Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
authors: María
authors: M
authors: Rodriguez-Soler
authors: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.
authors: Joan
authors: J
authors: Brunet
authors: Hereditary Cancer Program and.
authors: Sara
authors: S
authors: González
authors: Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
authors: Rodrigo
authors: R
authors: Jover
authors: Hereditary Cancer Program and.
authors: Conxi
authors: C
authors: Lázaro
authors: Hereditary Cancer Program and.
authors: Gabriel
authors: G
authors: Capellá
authors: Hereditary Cancer Program and.
authors: Marta
authors: M
authors: Pineda
authors: Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
authors: José Luís
authors: JL
authors: Soto
authors: Hereditary Cancer Program and.
authors: Ignacio
authors: I
authors: Blanco
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D015179:Colorectal Neoplasms / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human