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Oncotarget. 2017 Apr 18;8(16):26732-26743. doi: 10.18632/oncotarget.15810.

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

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Gastroenterology 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.
Biomedical Sciences Department, School of Medicine, University de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
Galician 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.
Department of Pathology, Hospital Clinic, Biobanc Clinic-IDIBAPS, Barcelona, Catalonia, Spain.
Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany.
Leiden University Medical Center (LUMC), Leiden, Netherlands.
Gastroenterology 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.
High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d'Hebron and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Terrassa, Barcelona, Spain.
Clinical Oncology Department, Corporacio Parc Tauli, Sabadell, Barcelona, Spain.
Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Biomédica Ourense, Pontevedra y Vigo, Ourense, Spain.


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.


POLD1; POLE; colorectal adenoma; colorectal neoplasm; genetic predisposition to disease

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