A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine
| Autor: | Inga Bjørnevoll, M. Hansen, Finn Drabløs, Anna Elisabeth Sylvander, Pål Sætrom, Arne K. Sandvik, Kristin Solum Steinsbekk, Wenche Sjursen, Jostein Johansen |
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| Jazyk: | angličtina |
| Předmět: |
Male
Heterozygote Cancer Research Colorectal cancer Molecular Sequence Data DNA polymerase epsilon Biology Germline mutation Mutation Carrier Intestine Small medicine Genetics Humans Exome Genetic Predisposition to Disease Genetics(clinical) Amino Acid Sequence Poly-ADP-Ribose Binding Proteins Genetics (clinical) Exome sequencing Ovarian Neoplasms Polymerase epsilon Sequence Homology Amino Acid Cancer DNA Polymerase II medicine.disease Pedigree Pancreatic Neoplasms Oncology Mutation (genetic algorithm) Mutation POLE Female Original Article Colorectal Neoplasms |
| Zdroj: | Familial Cancer |
| ISSN: | 1389-9600 |
| DOI: | 10.1007/s10689-015-9803-2 |
| Popis: | In some families there is an increased risk for colorectal cancer, caused by heritable, but often unidentified genetic mutations predisposing to the disease. We have identified the likely genetic cause for disease predisposition in a large family with high burden of colorectal adenomas and carcinomas, in addition to extra-colonic cancers. This family had previously been tested for known cancer susceptibility genes, with negative results. Exome sequencing was used to identify a novel mutation, c.1373A>T (p.Tyr458Phe), in the gene for DNA polymerase epsilon catalytic subunit (POLE). This mutation is located in the active site of the exonuclease domain of the enzyme, and affects a residue that has previously been shown to be important for exonuclease activity. The first predisposing mutation identified in POLE (c.1270C>G, p.Leu424Val) was associated with colorectal cancer only, but another mutation with a broader tumour spectrum (c.1089C>A, p.Asn363Lys) has recently been reported. In the family described in the present study, carriers generally have multiple colorectal adenomas and cancer of colon, pancreas, ovaries and small intestine which represents an important broadening of the tumour spectrum of POLE mutation carriers. We also observe a large phenotypic variation among the POLE mutation carriers in this family, most likely explained by modifying variants in other genes. One POLE mutation carrier has a novel variant in EXO1 (c.458C>T, p.Ala153Val), which may contribute to a more severe phenotype. The findings in this study will have important implications for risk assessment and surveillance of POLE mutation carriers. Electronic supplementary material The online version of this article (doi:10.1007/s10689-015-9803-2) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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