POLE, POLD1 and RNF43 screening in a serrated polyposis syndrome cohort

Yasmin Soares de Lima1, Coral Arnau-Collell1, Marcos Días-Gay1, Sabella Carballal1, Laia Bonjoch1, Leticia Moreira1, Juan José Lozano2, Teresa Ocaña1, Miriam Cuatrecasas Barcelona3, Aránzazu Díaz de Bustamante4, Antoni Castells1, Luis Bujanda5, Joaquín Cubiella6, Daniel Rodríguez-Alcalde7, Francesc Balaguer1, Clara Ruiz-Ponte8, Laura Valle9, Victor Moreno10, Castellví-Bel Sergi1

1Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Barcelona, Spain. 2Bioinformatics Platform, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 3Pathology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) and Tumor Bank-Biobank, Hospital Clínic, Barcelona, Spain. 4Genetics Unit, Hospital Universitario de Móstoles, Madrid, Spain. 5Gastroenterology 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. 6Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitaria Galicia Sur, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Ourense, Spain. 7Digestive Disease Section, Hospital Universitario de Móstoles, Móstoles, Spain. 8Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica_USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain. 9Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. 10Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Centro de Investigación Biomédica en Red de Epidemiologia y Salud Pública (CIBERESP), University of Barcelona, Barcelona, Spain

Abstract

Objectives

Serrated polyposis syndrome (SPS) is a condition characterised by multiple polyps  and colorectal cancer (CRC) predisposition. RNF43 has been recently related to SPS, and POLE and POLD1 to multiple polyposis predisposition. In this work, we aimed at screening potentially pathogenic mutations in those genes in a SPS cohort.

 

Methods

POLE, POLD1 and RNF43 were evaluated in a initial cohort of 16 SPS families that underwent whole-exome sequencing. A subsequent cohort of 211 SPS patients were analysed for the same genes included in a custom panel. Data was analyzed with a bioinformatics pipeline and annotated with different database information. Missense and truncation variants were prioritised using allele frequency and pathogenicity predictions. Then, variants were validated by Sanger sequencing.

Results

Potentially pathogenic genetic variants were identified in all genes. Frameshift variants were identified in POLE and POLD1, and an stop gained variant was detected in RNF43. Eleven missense variants were identified in POLE but not in the other genes. One synonymous variant was also found in RNF43. To date, all variants are labeled as of uncertain significance.

Conclusions

RNF43 variants are a very rare contributor to SPS germline predisposition. POLE and POLD1 variants may predispose in some cases to SPS although additional studies are needed. For instance, POLE variants outside the exonuclease domain and frameshift variants in both genes deserve to be further characterised by state-of-the-art functional studies.

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