Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in patients with colorectal adenomas and carcinomas. I. Spier1, S. Holzapfel1, J. Altmüller2,3, B. Zhao4, S. Horpaopan1, S. Vogt1,5, S. Chen4, M. Morak6,7, S. Raeder1, K. Kayser1, D. Stienen1, R. Adam1, P. Nürnberg2, G. Plotz8, E. Holinski-Feder6,7, R. P. Lifton4, H. Thiele2, P. Hoffmann1,9,10, V. Steinke1, S. Aretz1 1) Institute of Human Genetics, University of Bonn, Bonn, Germany; 2) Cologne Center for Genomics, University of Cologne, Germany; 3) Institute of Human Genetics, University of Cologne, Germany; 4) Departments of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA; 5) MVZ Dr. Eberhard & Partner, Dortmund, Germany; 6) Medizinische Klinik - Campus Innenstadt, Klinikum der LMU, Munich, Germany; 7) MGZ - Center of Medical Genetics, Munich, Germany; 8) Medizinische Klinik 1, Biomedical Research Laboratory, University of Frankfurt, Germany; 9) Department of Genomics, Life & Brain Center, University of Bonn, Germany; 10) Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.

   Purpose: 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. Methods: Targeted next-generation sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3, and POLE4 was performed (Illumina platform) using a sample of 241 unrelated patients (194 mutation negative polyposis patients and 47 familial colorectal carcinoma (CRC) cases with microsatellite stable tumours meeting the Amsterdam criteria). Data analysis was done by standard protocols using the VARBANK pipeline (CCG, Cologne). Results: The previously described pathogenic POLE mutation c.1270C>G;p.Leu424Val was detected in three families. The mutation was present in 1% (3/241) of all unrelated patients, and 7% (2/28) of familial polyposis cases. The colorectal phenotype in 13 affected mutation carriers (age at diagnosis 16-63 years) ranged from typical adenomatous polyposis to a Lynch syndrome-like manifestation, with high intrafamilial variability. The occurrence of multiple CRCs was common. Most patients (63%) had duodenal adenomas, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions including ovarian cancer and glioblastomas were evident. Nine further putative pathogenic variants were identified in four polymerase genes. The most promising was a de novo missense mutation in POLE (c.1306C>T;p.Pro436Ser). Conclusion: A PPAP was identified in a substantial number of our well characterized sample of polyposis and familial colorectal cancer patients. Screening for these 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 demonstrated a considerable clinical overlap between tumor syndromes based on mutations in DNA repair genes. In addition, we identified novel, potentially pathogenic variants in four polymerase genes. (Supported by German Cancer Aid, BONFOR programme of the University of Bonn and NIH Centers for Mendelian Genomics).

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