Format

Send to

Choose Destination
Eur J Hum Genet. 2015 Aug;23(8):1080-4. doi: 10.1038/ejhg.2014.242. Epub 2014 Nov 5.

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.

Author information

1
Department of Pathology, LUMC, Leiden, The Netherlands.
2
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Department of Clinical Genetics, LUMC, Leiden, The Netherlands.
4
1] Department of Clinical Genetics, LUMC, Leiden, The Netherlands [2] Department of Human Genetics, LUMC, Leiden, The Netherlands.
5
1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands [2] Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
6
Department of Gastroenterology, LUMC, Leiden, The Netherlands.

Abstract

Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C>G, p.(Leu424Val) and POLD1 c.1433G>A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant.

PMID:
25370038
PMCID:
PMC4351893
DOI:
10.1038/ejhg.2014.242
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center