A mutation in POLE predisposing to a multi-tumour phenotype
Journal article, 2014

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.



colorectal cancer

exome sequencing


Anna Rohlin

University of Gothenburg

Theofanis Zagoras

University of Gothenburg

Staffan Nilsson

University of Gothenburg

Chalmers, Mathematical Sciences, Mathematical Statistics

Ulf Lundstam

University of Gothenburg

Jan Wahlström

University of Gothenburg

Leif Hultén

University of Gothenburg

Tommy Martinsson

University of Gothenburg

B Göran Karlsson

University of Gothenburg

Margareta Nordling

University of Gothenburg

International Journal of Oncology

1019-6439 (ISSN)

Vol. 45 1 77-81

Areas of Advance

Life Science Engineering (2010-2018)

Subject Categories

Cancer and Oncology



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