title: Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.
abstract: In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA.
authors.forename: Bixiao
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|MVZ Dr. Eberhard & Partner, Dortmund, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Vogt
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Chen
authors.affiliation: Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany.|MGZ-Center of Medical Genetics, Munich, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Morak
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raeder
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kayser
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Adam
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Medizinische Klinik 1, Biomedical Research Laboratory, University of Frankfurt, Frankfurt, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Plotz
authors.affiliation: Medizinische Klinik-Campus Innenstadt, Klinikum der LMU, Munich, Germany.|MGZ-Center of Medical Genetics, Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D004257:DNA Polymerase II / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010739:Phospholipase D / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D007527:Isoenzymes; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; D004259:DNA-Directed DNA Polymerase; C119525:POLE protein, human; D010739:Phospholipase D
keywords: Lynch syndrome; adenomatous polyposis; familial colorectal cancer; gastrointestinal polyposis syndromes; next-generation sequencing