Research Papers:

POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer

Clara Esteban-Jurado, David Giménez-Zaragoza, Jenifer Muñoz, Sebastià Franch-Expósito, Miriam Álvarez-Barona, Teresa Ocaña, Miriam Cuatrecasas, Sabela Carballal, María López-Cerón, Maria Marti-Solano, Marcos Díaz-Gay, Tom van Wezel, Antoni Castells, Luis Bujanda, Judith Balmaña, Victoria Gonzalo, Gemma Llort, Clara Ruiz-Ponte, Joaquín Cubiella, Francesc Balaguer, Rosa Aligué and Sergi Castellví-Bel _

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Oncotarget. 2017; 8:26732-26743. https://doi.org/10.18632/oncotarget.15810

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Clara Esteban-Jurado1, David Giménez-Zaragoza2, Jenifer Muñoz1, Sebastià Franch-Expósito1, Miriam Álvarez-Barona3, Teresa Ocaña1, Miriam Cuatrecasas4, Sabela Carballal1, María López-Cerón1, Maria Marti-Solano5, Marcos Díaz-Gay1, Tom van Wezel6, Antoni Castells1, Luis Bujanda7, Judith Balmaña8, Victoria Gonzalo9, Gemma Llort10, Clara Ruiz-Ponte3, Joaquín Cubiella11, Francesc Balaguer1, Rosa Aligué2, Sergi Castellví-Bel1

1Gastroenterology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Catalonia, Spain

2Biomedical Sciences Department, School of Medicine, University de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

3Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain

4Department of Pathology, Hospital Clinic, Biobanc Clinic-IDIBAPS, Barcelona, Catalonia, Spain

5Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany

6Leiden University Medical Center (LUMC), Leiden, Netherlands

7Gastroenterology Department, Hospital Donostia–Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Basque Country University (UPV/EHU), San Sebastián, Spain

8High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain

9Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Terrassa, Barcelona, Spain

10Clinical Oncology Department, Corporacio Parc Tauli, Sabadell, Barcelona, Spain

11Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Biomédica Ourense, Pontevedra y Vigo, Ourense, Spain

Correspondence to:

Sergi Castellví-Bel, email: [email protected]

Keywords: colorectal neoplasm, colorectal adenoma, genetic predisposition to disease, POLE, POLD1

Received: January 04, 2017     Accepted: February 18, 2017     Published: March 01, 2017


Germline mutations in POLE and POLD1 have been shown to cause predisposition to colorectal multiple polyposis and a wide range of neoplasms, early-onset colorectal cancer being the most prevalent. In order to find additional mutations affecting the proofreading activity of these polymerases, we sequenced its exonuclease domain in 155 patients with multiple polyps or an early-onset colorectal cancer phenotype without alterations in the known hereditary colorectal cancer genes. Interestingly, none of the previously reported mutations in POLE and POLD1 were found. On the other hand, among the genetic variants detected, only two of them stood out as putative pathogenic in the POLE gene, c.1359 + 46del71 and c.1420G > A (p.Val474Ile). The first variant, detected in two families, was not proven to alter correct RNA splicing. Contrarily, c.1420G > A (p.Val474Ile) was detected in one early-onset colorectal cancer patient and located right next to the exonuclease domain. The pathogenicity of this change was suggested by its rarity and bioinformatics predictions, and it was further indicated by functional assays in Schizosaccharomyces pombe. This is the first study to functionally analyze a POLE genetic variant outside the exonuclease domain and widens the spectrum of genetic changes in this DNA polymerase that could lead to colorectal cancer predisposition.

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