Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Issue 2 (20th January 2015)

• Record Type: Journal Article
• Authors: Spier, Isabel; Holzapfel, Stefanie; Altmüller, Janine; Zhao, Bixiao; Horpaopan, Sukanya; Vogt, Stefanie; Chen, Sophia; Morak, Monika; Raeder, Susanne; Kayser, Katrin; Stienen, Dietlinde; Adam, Ronja; Nürnberg, Peter; Plotz, Guido; Holinski‐Feder, Elke; Lifton, Richard P.; Thiele, Holger; Hoffmann, Per; Steinke, Verena; Aretz, Stefan
• Is Part Of: International journal of cancer. Volume 137:Issue 2(2015:Jul. 15)
• Page Start: 320
• Page End: 331
• Publication Date: 2015-01-20
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.29396
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the <italic>APC</italic>, <italic>MUTYH</italic>, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes <italic>POLE</italic> and <italic>POLD1</italic> 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 <italic>POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3</italic> and <italic>POLE4</italic> was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The <italic>POLE</italic> 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 <italic>POLE</italic>. 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.</p> </abstract>