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Hum Mol Genet. 2014 Jul 1;23(13):3506-12. doi: 10.1093/hmg/ddu058. Epub 2014 Feb 5.

New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.

Author information

Hereditary Cancer Program and
Research Laboratory.
Hereditary Cancer Program and.
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
Department of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.
Department of Pathology and.
Hereditary Cancer Unit, La Fe University Hospital, Valencia, Spain.
Hereditary Cancer Unit, Valencian Institute of Oncology, Valencia, Spain and.
Department of Gastroenterology, Alicante University Hospital, Alicante, Spain.
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain.


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.

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