POLEandPOLD1screening in 155 patients with multiple polyps and early-onset colorectal cancer

// Clara Esteban-Jurado 1 , David Gimenez-Zaragoza 2 , Jenifer Munoz 1 , Sebastia Franch-Exposito 1 , Miriam Alvarez-Barona 3 , Teresa Ocana 1 , Miriam Cuatrecasas 4 , Sabela Carballal 1 , Maria Lopez-Ceron 1 , Maria Marti-Solano 5 , Marcos Diaz-Gay 1 , Tom van Wezel 6 , Antoni Castells 1 , Luis Bujanda 7 , Judith Balmana 8 , Victoria Gonzalo 9 , Gemma Llort 10 , Clara Ruiz-Ponte 3 , Joaquin Cubiella 11 , Francesc Balaguer 1 , Rosa Aligue 2 , Sergi Castellvi-Bel 1 1 Gastroenterology Department, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Catalonia, Spain 2 Biomedical Sciences Department, School of Medicine, University de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain 3 Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clinico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain 4 Department of Pathology, Hospital Clinic, Biobanc Clinic-IDIBAPS, Barcelona, Catalonia, Spain 5 Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany 6 Leiden University Medical Center (LUMC), Leiden, Netherlands 7 Gastroenterology Department, Hospital Donostia–Instituto Biodonostia, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Basque Country University (UPV/EHU), San Sebastian, Spain 8 High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain 9 Gastroenterology Department, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain 10 Clinical Oncology Department, Corporacio Parc Tauli, Sabadell, Barcelona, Spain 11 Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigacion Biomedica Ourense, Pontevedra y Vigo, Ourense, Spain Correspondence to: Sergi Castellvi-Bel, email: sbel@clinic.cat Keywords: colorectal neoplasm, colorectal adenoma, genetic predisposition to disease, POLE, POLD1 Received: January 04, 2017 Accepted: February 18, 2017 Published: March 01, 2017 ABSTRACT 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.