International journal of cancer, 2015-07-15, Vol.137 (2), p.320-331
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.
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.
adenomatous polyposis ; next‐generation sequencing ; familial colorectal cancer ; gastrointestinal polyposis syndromes ; Lynch syndrome ; Adenoma - genetics ; Colorectal Neoplasms - genetics ; Humans ; Middle Aged ; Family Health ; Male ; Mutation, Missense ; DNA-Directed DNA Polymerase - genetics ; Young Adult ; Poly-ADP-Ribose Binding Proteins ; Adenoma - enzymology ; Aged, 80 and over ; Germ-Line Mutation ; Adult ; Female ; Phospholipase D - genetics ; Child ; DNA Polymerase II - genetics ; Colorectal Neoplasms - enzymology ; Genetic Predisposition to Disease - genetics ; Isoenzymes - genetics ; Gene Frequency ; Phenotype ; Pedigree ; Adolescent ; Aged ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA - methods ; Gene mutations ; Genes ; Colorectal cancer ; Genetic research ; Genetic aspects ; Diagnosis ; Cancer ; Index Medicus
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