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A mutation in POLE predisposing to a multi-tumour phenotype

Anna Rohlin ; Theofanis Zagoras ; Staffan Nilsson (Institutionen för matematiska vetenskaper, matematisk statistik) ; Ulf Lundstam ; Jan Wahlström ; Leif Hultén ; Tommy Martinsson ; B Göran Karlsson ; Margareta Nordling
International Journal of Oncology (1019-6439). Vol. 45 (2014), 1, p. 77-81.
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: colorectal cancer; mutation; POLE; exome sequencing



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Denna post skapades 2014-07-03. Senast ändrad 2015-02-13.
CPL Pubid: 200115

 

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Institutioner (Chalmers)

Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik (GU)
Institutionen för matematiska vetenskaper, matematisk statistik (2005-2016)
Institutionen för kliniska vetenskaper, sektionen för kirurgi och kirurgisk gastroforskning, Avdelningen för kirurgi (GU)
Svenskt NMR-centrum vid Göteborgs universitet (GU)

Ämnesområden

Livsvetenskaper
Cancer och onkologi

Chalmers infrastruktur