A mutation in POLE predisposing to a multi-tumour phenotype.
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.
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
Anna
A
Rohlin
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
Theofanis
T
Zagoras
Mathematical Sciences, Chalmers University of Technology, SE 412 96 Gothenburg, Sweden.
Staffan
S
Nilsson
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden.
Ulf
U
Lundstam
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
Jan
J
Wahlström
The Colorectal Unit, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden.
Leif
L
Hultén
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
Tommy
T
Martinsson
The Swedish NMR‑Centre, University of Gothenburg, SE 413 45 Gothenburg, Sweden.
Göran B
GB
Karlsson
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden.
Margareta
M
Nordling
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000368:Aged; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004257:DNA Polymerase II / Q000235:genetics* / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D055847:Lynch Syndrome II / Q000235:genetics* / Q000473:pathology; D008297:Male; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation
D004257:DNA Polymerase II; D005090:Exodeoxyribonucleases