<i>POLE</i>and<i>POLD1</i>screening in 155 patients with multiple polyps and early-onset colorectal cancer

Abstract

// Clara Esteban-Jurado 1 , David Gim&eacute;nez-Zaragoza 2 , Jenifer Mu&ntilde;oz 1 , Sebasti&agrave; Franch-Exp&oacute;sito 1 , Miriam &Aacute;lvarez-Barona 3 , Teresa Oca&ntilde;a 1 , Miriam Cuatrecasas 4 , Sabela Carballal 1 , Mar&iacute;a L&oacute;pez-Cer&oacute;n 1 , Maria Marti-Solano 5 , Marcos D&iacute;az-Gay 1 , Tom van Wezel 6 , Antoni Castells 1 , Luis Bujanda 7 , Judith Balma&ntilde;a 8 , Victoria Gonzalo 9 , Gemma Llort 10 , Clara Ruiz-Ponte 3 , Joaqu&iacute;n Cubiella 11 , Francesc Balaguer 1 , Rosa Aligu&eacute; 2 , Sergi Castellv&iacute;-Bel 1 1 Gastroenterology Department, Hospital Cl&iacute;nic, Institut d&rsquo;Investigacions Biom&egrave;diques August Pi i Sunyer (IDIBAPS), Centro de Investigaci&oacute;n Biom&eacute;dica en Red de Enfermedades Hep&aacute;ticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Catalonia, Spain 2 Biomedical Sciences Department, School of Medicine, University de Barcelona, Institut d&rsquo;Investigacions Biom&egrave;diques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain 3 Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigaci&oacute;n Biom&eacute;dica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Cl&iacute;nico, 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&ndash;Instituto Biodonostia, Centro de Investigaci&oacute;n Biom&eacute;dica en Red de Enfermedades Hep&aacute;ticas y Digestivas (CIBEREHD), Basque Country University (UPV/EHU), San Sebasti&aacute;n, Spain 8 High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d&rsquo;Hebron and Vall d&rsquo;Hebron Institute of Oncology, Barcelona, Spain 9 Gastroenterology Department, Hospital Universitari M&uacute;tua 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 Investigaci&oacute;n Biom&eacute;dica Ourense, Pontevedra y Vigo, Ourense, Spain Correspondence to: Sergi Castellv&iacute;-Bel, email: sbel@clinic.cat Keywords: colorectal neoplasm, colorectal adenoma, genetic predisposition to disease, POLE, POLD1 Received: January 04, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 18, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 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 &gt; A (p.Val474Ile). The first variant, detected in two families, was not proven to alter correct RNA splicing. Contrarily, c.1420G &gt; 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.