Show simple item record

dc.contributor.authorStefansson, Olafur Andri
dc.contributor.authorHermanowicz, Stefan
dc.contributor.authorvan der Horst, Jasper
dc.contributor.authorHilmarsdottir, Holmfridur
dc.contributor.authorStaszczak, Zuzanna
dc.contributor.authorJonasson, Jon Gunnlaugur
dc.contributor.authorTryggvadottir, Laufey
dc.contributor.authorGudjonsson, Thorkell
dc.contributor.authorSigurdsson, Stefan
dc.date.accessioned2017-08-28T14:54:07Z
dc.date.available2017-08-28T14:54:07Z
dc.date.issued2017-07-05
dc.date.submitted2017
dc.identifier.citationCpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer. 2017, 17 (1):469 BMC Canceren
dc.identifier.issn1471-2407
dc.identifier.pmid28679371
dc.identifier.doi10.1186/s12885-017-3453-8
dc.identifier.urihttp://hdl.handle.net/2336/620285
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Filesen
dc.description.abstractDNA repair of alkylation damage is defective in various cancers. This occurs through somatically acquired inactivation of the MGMT gene in various cancer types, including breast cancers. In addition to MGMT, the two E. coli AlkB homologs ALKBH2 and ALKBH3 have also been linked to direct reversal of alkylation damage. However, it is currently unknown whether ALKBH2 or ALKBH3 are found inactivated in cancer.
dc.description.abstractMethylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation. TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3. DNA methylation analysis for the ALKBH3 promoter region was carried out by pyrosequencing (PyroMark Q24) in 265 primary breast tumours and 30 proximal normal breast tissue samples along with 8 breast-derived cell lines. ALKBH3 mRNA and protein expression were analysed in cell lines using RT-PCR and Western blotting, respectively. DNA alkylation damage assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical parameters and survival outcomes in patients were obtained and assessed in relation to ALKBH3 promoter methylation.
dc.description.abstractThe ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer. We developed a quantitative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels of alkylation damage in association with epigenetic inactivation of the ALKBH3 gene (P = 0.029). In our cohort of 265 primary breast cancer, we found 72 cases showing aberrantly high CpG promoter methylation over the ALKBH3 promoter (27%; 72 out of 265). We further show that increasingly higher degree of ALKBH3 promoter methylation is associated with reduced breast-cancer specific survival times in patients. In this analysis, ALKBH3 promoter methylation at >20% CpG methylation was found to be statistically significantly associated with reduced survival (HR = 2.3; P = 0.012). By thresholding at the clinically relevant CpG methylation level (>20%), we find the incidence of ALKBH3 promoter methylation to be 5% (13 out of 265).
dc.description.abstractALKBH3 is a novel addition to the catalogue of DNA repair genes found inactivated in breast cancer. Our results underscore a link between defective alkylation repair and breast cancer which, additionally, is found in association with poor disease outcome.
dc.description.sponsorshipIcelandic Centre for Researchen
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttps://bmccancer.biomedcentral.com/track/pdf/10.1186/s12885-017-3453-8?site=bmccancer.biomedcentral.comen
dc.rightsArchived with thanks to BMC canceren
dc.subjectBrjóstakrabbameinen
dc.subjectGenen
dc.subjectPTT12en
dc.subject.meshDNA Repairen
dc.subject.meshBreast Neoplasmsen
dc.titleCpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.en
dc.typeArticleen
dc.contributor.department[ 1 ] Biomed Ctr, Canc Res Lab, Vatnsmyrarvegur 16 4th Floor, IS-101 Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 2 ] Univ Iceland, Fac Med, Vatnsmyrarvegur 16 4th Floor, IS-101 Reykjavik, Iceland [ 3 ] Biomed Ctr, Dept Biochem & Mol Biol, Vatnsmyrarvegur 16 5th Floor, IS-101 Reykjavik, Iceland [ 4 ] Iceland Canc Registry, Skogarhlid 8, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 5 ] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Icelanden
dc.identifier.journalBMC canceren
dc.rights.accessOpen Access - Opinn aðganguren
refterms.dateFOA2018-09-12T16:40:00Z
html.description.abstractDNA repair of alkylation damage is defective in various cancers. This occurs through somatically acquired inactivation of the MGMT gene in various cancer types, including breast cancers. In addition to MGMT, the two E. coli AlkB homologs ALKBH2 and ALKBH3 have also been linked to direct reversal of alkylation damage. However, it is currently unknown whether ALKBH2 or ALKBH3 are found inactivated in cancer.
html.description.abstractMethylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation. TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3. DNA methylation analysis for the ALKBH3 promoter region was carried out by pyrosequencing (PyroMark Q24) in 265 primary breast tumours and 30 proximal normal breast tissue samples along with 8 breast-derived cell lines. ALKBH3 mRNA and protein expression were analysed in cell lines using RT-PCR and Western blotting, respectively. DNA alkylation damage assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical parameters and survival outcomes in patients were obtained and assessed in relation to ALKBH3 promoter methylation.
html.description.abstractThe ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer. We developed a quantitative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels of alkylation damage in association with epigenetic inactivation of the ALKBH3 gene (P = 0.029). In our cohort of 265 primary breast cancer, we found 72 cases showing aberrantly high CpG promoter methylation over the ALKBH3 promoter (27%; 72 out of 265). We further show that increasingly higher degree of ALKBH3 promoter methylation is associated with reduced breast-cancer specific survival times in patients. In this analysis, ALKBH3 promoter methylation at >20% CpG methylation was found to be statistically significantly associated with reduced survival (HR = 2.3; P = 0.012). By thresholding at the clinically relevant CpG methylation level (>20%), we find the incidence of ALKBH3 promoter methylation to be 5% (13 out of 265).
html.description.abstractALKBH3 is a novel addition to the catalogue of DNA repair genes found inactivated in breast cancer. Our results underscore a link between defective alkylation repair and breast cancer which, additionally, is found in association with poor disease outcome.


Files in this item

Thumbnail
Name:
CpG promoter ....pdf
Size:
1.887Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record