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

Laura Valle, Eva Hernández-Illán, Fernando Bellido, Gemma Aiza, Adela Castillejo, María Isabel Castillejo, Matilde Navarro, Nuria Seguí, Gardenia Vargas, Carla Guarinos, Miriam Juarez, Xavier Sanjuán, Silvia Iglesias, Cristina Alenda, Cecilia Egoavil, Ángel Segura, María José Juan, María Rodriguez-Soler, Joan Brunet, Sara GonzálezRodrigo Jover, Conxi Lázaro, Gabriel Capellá, Marta Pineda, José Luís Soto, Ignacio Blanco

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125 Scopus citations


Germline mutations in DNA polymerase ε (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-onsetCRC 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 amismatch 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.

Original languageEnglish
Article numberddu058
Pages (from-to)3506-3512
Number of pages7
JournalHuman Molecular Genetics
Issue number13
StatePublished - Jul 2014
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Spanish Ministry of Economy and Competitiveness (State Secretariat for Research, Development and Innovation) (SAF2012-38885 to L.V.); the Spanish Ministry of Health and the Carlos III Health Institute (FIS PI08/0726 to R.J.); L’Oréal-UNESCO ‘For Women in Science’; the Scientific Foundation Asociación Española Contra el Cáncer; and the Government of Catalonia (2009SGR290). L.V. is a recipient of a Ramón y Cajal contract and F.B. of a fellowship both from the Spanish Ministry of Economy and Competitiveness. E.H.-I. and N.S. hold fellowships from the Carlos III Health Institute and C.G. from the Con-selleria d’Educació of the Valencian Autonomous Community.


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