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Carcinogenesis Advance Access published online on May 14, 2009
Carcinogenesis, doi:10.1093/carcin/bgp118
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Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

Monika Forsbring1, Erik S. Vik1, Bjørn Dalhus2, Tom H. Karlsen3, Annika Bergquist4, Erik Schrumpf3, Magnar Bjørås1,2, Kirsten M. Boberg3 and Ingrun Alseth1,*

1 Institute of Medical Microbiology, Rikshospitalet University Hospital HF and Centre for Molecular Biology and Neuroscience, University of Oslo, N-0027 Oslo, Norway
2 Institute of Clinical Biochemistry, University of Oslo, N-0027 Oslo, Norway
3 Medical Department, Rikshospitalet University Hospital HF, N-0027 Oslo, Norway
4 Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, S-14186 Stockholm, Sweden

* For correspondence: E-mail ingrun.alseth{at}rr-research.no; Tel (+47) 23074069; Fax (+47) 23074061

The human hMYH and NEIL1 genes encode DNA glycosylases involved in repair of oxidative base damage and mutations in these genes are associated with certain cancers. Primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease characterised by inflammatory destruction of the biliary tree, is often complicated by the development of cholangiocarcinoma (CCA). Here we aimed to investigate the influence of genetic variations in the hMYH and NEIL1 genes on risk of CCA in PSC patients. The hMYH and NEIL1 gene loci in addition to the DNA repair genes hOGG1 NTHL1 and NUDT1 were analysed in 66 PSC patients (37 with CCA and 29 without cancer) by complete genomic sequencing of exons and adjacent intronic regions. Several single nucleotide polymorphisms and mutations were identified and severe impairment of protein function was observed for 3 non-synonymous variants. The NEIL1 G83D mutant was dysfunctional for the major oxidation products 8oxoguanine (8oxoG), thymine glycol and dihydrothymine in duplex DNA, and the ability to perform {delta}-elimination at abasic sites was significantly reduced. The hMYH R260Q mutant had severe defect in adenine DNA glycosylase activity whereas hMYH H434D could excise adenines from A:8oxoG pairs, but not from A:G mispairs. We found no overall associations between the 18 identified variants and susceptibility to CCA in PSC patients, however the impaired variants may be of significance for carcinogenesis in general. Our findings demonstrate the importance of complete resequencing of selected candidate genes in order to identify rare genetic variants and their possible contribution to individual susceptibility to cancer development.

Key Words: primary sclerosing cholangitis • cholangiocarcinoma • oxidative DNA damage • base excision repair • DNA glycosylase

Received September 25, 2008; revised May 4, 2009; accepted May 8, 2009.


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