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A mutation in POLE predisposing to a multi-tumour phenotype

Journal article
Authors Anna Rohlin
Theofanis Zagoras
Staffan Nilsson
Ulf Lundstam
Jan Wahlström
Leif Hultén
Tommy Martinsson
B Göran Karlsson
Margareta Nordling
Published in International Journal of Oncology
Volume 45
Issue 1
Pages 77-81
ISSN 1019-6439
Publication year 2014
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Clinical Sciences, Department of Surgery
Department of Mathematical Sciences, Mathematical Statistics
Swedish NMR Centre at Göteborg University
Pages 77-81
Language en
Keywords colorectal cancer; mutation; POLE; exome sequencing
Subject categories Cancer and Oncology


Somatic mutations in the POLE gene encoding the catalytic subunit of DNA polymerase epsilon 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.

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