Format

Send to

Choose Destination
Int J Oncol. 2014 Jul;45(1):77-81. doi: 10.3892/ijo.2014.2410. Epub 2014 Apr 29.

A mutation in POLE predisposing to a multi-tumour phenotype.

Author information

1
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
2
Mathematical Sciences, Chalmers University of Technology, SE 412 96 Gothenburg, Sweden.
3
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden.
4
The Colorectal Unit, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden.
5
The Swedish NMR‑Centre, University of Gothenburg, SE 413 45 Gothenburg, Sweden.

Abstract

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.

PMID:
24788313
PMCID:
PMC4079162
DOI:
10.3892/ijo.2014.2410
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Spandidos Publications Icon for PubMed Central
Loading ...
Support Center