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

• Published in: Oncotarget Vol. 8; no. 16; pp. 26732 - 26743
• Main Authors: Esteban-Jurado, Clara, Giménez-Zaragoza, David, Muñoz, Jenifer, Franch-Expósito, Sebastià, Álvarez-Barona, Miriam, Ocaña, Teresa, Cuatrecasas, Miriam, Carballal, Sabela, López-Cerón, María, Marti-Solano, Maria, Díaz-Gay, Marcos, van Wezel, Tom, Castells, Antoni, Bujanda, Luis, Balmaña, Judith, Gonzalo, Victoria, Llort, Gemma, Ruiz-Ponte, Clara, Cubiella, Joaquín, Balaguer, Francesc, Aligué, Rosa, Castellví-Bel, Sergi
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 18-04-2017
• Subjects: Adenomatous Polyposis Coli - diagnosis; Adenomatous Polyposis Coli - genetics; Adolescent; Adult; Age of Onset; Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Child; Child, Preschool; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - prevention & control; DNA Polymerase II - chemistry; DNA Polymerase II - genetics; DNA Polymerase III - chemistry; DNA Polymerase III - genetics; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant; Infant, Newborn; Male; Middle Aged; Models, Molecular; Mutation; Pedigree; Poly-ADP-Ribose Binding Proteins - chemistry; Poly-ADP-Ribose Binding Proteins - genetics; Protein Conformation; Protein Domains - genetics; Research Paper; Young Adult; colorectal adenoma; genetic predisposition to disease; colorectal neoplasm; POLE; POLD1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.15810

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.