Universität zu Köln

Spier, Isabel, Holzapfel, Stefanie, Altmueller, Janine, Zhao, Bixiao ORCID: 0000-0002-1775-1690, Horpaopan, Sukanya, Vogt, Stefanie, Chen, Sophia, Morak, Monika, Raeder, Susanne, Kayser, Katrin, Stienen, Dietlinde, Adam, Ronja, Nuernberg, Peter, Plotz, Guido, Holinski-Feder, Elke, Lifton, Richard P., Thiele, Holger, Hoffmann, Per, Steinke, Verena and Aretz, Stefan ORCID: 0000-0002-5228-1890 (2015). Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int. J. Cancer, 137 (2). S. 320 - 332. HOBOKEN: WILEY-BLACKWELL. ISSN 1097-0215

Full text not available from this repository.

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. What's New? A substantial number of families with adenomatous polyposis and Lynch-like phenotype have no known underlying germline mutations. Recently new mutations in the genes encoding DNA polymerase epsilon and delta were identified. Here the authors characterize the frequency and phenotypic spectrum of this newly described polymerase proofreading-associated polyposis (PPAP) syndrome. They broadened the tumor spectrum to duodenal neoplasias, extraintestinal tumors and multiple colorectal carcinomas, underscoring the clinical relevance of this syndrome beyond adenomatous polyposis. In addition, they identified nine novel, potentially pathogenic variants in four polymerase genes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Bixiao UNSPECIFIED orcid.org/0000-0002-1775-1690 UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Morak, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Raeder, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Kayser, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Stienen, Dietlinde UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, Ronja UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Plotz, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Holinski-Feder, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Lifton, Richard P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinke, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-398821
DOI:	10.1002/ijc.29396
Journal or Publication Title:	Int. J. Cancer
Volume:	137
Number:	2
Page Range:	S. 320 - 332
Date:	2015
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUTYH-ASSOCIATED POLYPOSIS; DNA-POLYMERASE; LYNCH SYNDROME; STRUCTURAL BASIS; CANCER RISK; APC; DELTA; HNPCC; PREDISPOSE; MECHANISMS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39882