TY - JOUR AB - Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase ε have been found in sporadic colorectal cancers (CRCs) and are most likely of importance in tumour development and/or progression. Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE. The highly penetrant mutation was associated with predisposition to CRC only and no extra‑colonic tumours were observed. We have identified a mutation in a large family in which the carriers not only developed CRC, they also demonstrate a highly penetrant predisposition to extra-intestinal tumours such as ovarian, endometrial and brain tumours. The mutation, NM_006231.2:c.1089C>A, p.Asn363Lys, also located in the proofreading exonuclease domain is directly involved in DNA binding. Theoretical prediction of the amino acid substitution suggests a profound effect of the substrate binding capability and a more severe impairment of the catalytic activity compared to the previously reported germline mutation. A possible genotype to phenotype correlation for deleterious mutations in POLE might exist that needs to be considered in the follow-up of mutation carriers. AD - Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden Mathematical Sciences, Chalmers University of Technology, SE 412 96 Gothenburg, Sweden Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden The Colorectal Unit, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden The Swedish NMR‑Centre, University of Gothenburg, SE 413 45 Gothenburg, Sweden AU - Rohlin,Anna AU - Zagoras,Theofanis AU - Nilsson,Staffan AU - Lundstam,Ulf AU - Wahlström,Jan AU - Hultén,Leif AU - Martinsson,Tommy AU - Karlsson,Göran,B. AU - Nordling,Margareta DA - 2014/07/01 DO - 10.3892/ijo.2014.2410 EP - 81 IS - 1 JO - Int J Oncol KW - colorectal cancer mutation POLE exome sequencing PY - 2014 SN - 1019-6439 1791-2423 SP - 77 ST - A mutation in POLE predisposing to a multi-tumour phenotype T2 - International Journal of Oncology TI - A mutation in POLE predisposing to a multi-tumour phenotype UR - https://doi.org/10.3892/ijo.2014.2410 VL - 45 ER -