A mutation in POLE predisposing to a multi-tumour phenotype

Rohlin,Anna; Zagoras,Theofanis; Nilsson,Staffan; Lundstam,Ulf; Wahlström,Jan; Hultén,Leif; Martinsson,Tommy; Karlsson,Göran B.; Nordling,Margareta

doi:10.3892/ijo.2014.2410

A mutation in POLE predisposing to a multi-tumour phenotype

Authors:
- Anna Rohlin
- Theofanis Zagoras
- Staffan Nilsson
- Ulf Lundstam
- Jan Wahlström
- Leif Hultén
- Tommy Martinsson
- Göran B. Karlsson
- Margareta Nordling
View Affiliations

Affiliations: Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden, Mathematical Sciences, Chalmers University of Technology, SE 412 96 Gothenburg, Sweden, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden , The Colorectal Unit, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, SE 416 85 Gothenburg, Sweden, The Swedish NMR‑Centre, University of Gothenburg, SE 413 45 Gothenburg, Sweden
Published online on: April 29, 2014 https://doi.org/10.3892/ijo.2014.2410
Pages: 77-81
Copyright: © Rohlin et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1.	Palles C, Cazier JB, Howarth KM, et al: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 45:136–144. 2013. View Article : Google Scholar : PubMed/NCBI
2.	Kanter-Smoler G, Bjork J, Fritzell K, et al: Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization. Clin Gastroenterol Hepatol. 4:499–506. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Li H and Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Li H, Handsaker B, Wysoker A, et al: The Sequence Alignment/Map format and SAMtools. Bioinformatics. 25:2078–2079. 2009. View Article : Google Scholar : PubMed/NCBI
5.	McKenna A, Hanna M, Banks E, et al: The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–1303. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Wang K, Li M and Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38:e1642010. View Article : Google Scholar : PubMed/NCBI
7.	Sherry ST, Ward MH, Kholodov M, et al: dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29:308–311. 2001. View Article : Google Scholar : PubMed/NCBI
8.	Liu X, Jian X and Boerwinkle E: dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat. 32:894–899. 2011. View Article : Google Scholar : PubMed/NCBI
9.	Kanehisa M, Goto S, Sato Y, Furumichi M and Tanabe M: KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40:102012. View Article : Google Scholar : PubMed/NCBI
10.	Ashburner M, Ball CA, Blake JA, et al: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet. 25:25–29. 2000.PubMed/NCBI
11.	Ruiz-Pesini E, Lott MT, Procaccio V, et al: An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res. 35:182007. View Article : Google Scholar : PubMed/NCBI
12.	Dreszer TR, Karolchik D, Zweig AS, et al: The UCSC Genome Browser database: extensions and updates 2011. Nucleic Acids Res (Database issue). 40:D918–D923. 2012. View Article : Google Scholar : PubMed/NCBI
13.	Beese LS and Steitz TA: Structural basis for the 3’-5’ exonuclease activity of Escherichia coli DNA polymerase I: a two metal ion mechanism. EMBO J. 10:25–33. 1991.
14.	Lin TC, Wang CX, Joyce CM and Konigsberg WH: 3’-5’ Exonucleolytic activity of DNA polymerases: structural features that allow kinetic discrimination between ribo- and deoxyribonucleotide residues. Biochemistry. 40:8749–8755. 2001.
15.	Nishioka M, Mizuguchi H, Fujiwara S, et al: Long and accurate PCR with a mixture of KOD DNA polymerase and its exonuclease deficient mutant enzyme. J Biotechnol. 88:141–149. 2001. View Article : Google Scholar : PubMed/NCBI
16.	Murphy K, Darmawan H, Schultz A, Fidalgo da Silva E and Reha-Krantz LJ: A method to select for mutator DNA polymerase deltas in Saccharomyces cerevisiae. Genome. 49:403–410. 2006. View Article : Google Scholar
17.	Abdus Sattar AK, Lin TC, Jones C and Konigsberg WH: Functional consequences and exonuclease kinetic parameters of point mutations in bacteriophage T4 DNA polymerase. Biochemistry. 35:16621–16629. 1996.PubMed/NCBI
18.	Flohr T, Dai JC, Buttner J, Popanda O, Hagmuller E and Thielmann HW: Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines. Int J Cancer. 80:919–929. 1999. View Article : Google Scholar : PubMed/NCBI
19.	Da Costa LT, Liu B, el-Deiry W, et al: Polymerase delta variants in RER colorectal tumours. Nat Genet. 9:10–11. 1995.PubMed/NCBI
20.	Yoshida R, Miyashita K, Inoue M, et al: Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer. Eur J Hum Genet. 19:320–325. 2011. View Article : Google Scholar : PubMed/NCBI
21.	Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI
22.	Hasselgren PO, Hulten L and Karlstrom L: ‘Cancer family syndrome’ - description of a family with a hereditary incidence of malignant tumors of the colon and other organs. Lakartidningen. 81:2451–2453. 1984.(In Swedish).
23.	Kopf I, Islam MQ, Friberg LG and Levan G: Familial occurrence of cancer and heteromorphism of the heterochromatic segment of chromosome 1. Hereditas. 110:79–83. 1989. View Article : Google Scholar : PubMed/NCBI