CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
AuthorsStefansson, Olafur Andri
van der Horst, Jasper
Jonasson, Jon Gunnlaugur
MetadataShow full item record
CitationCpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer. 2017, 17 (1):469 BMC Cancer
ÚtdrátturDNA 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.
Methylome 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.
The 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).
ALKBH3 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.
Lu00FDsingTo 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 Files
RightsArchived with thanks to BMC cancer
- DNA repair enzymes ALKBH2, ALKBH3, and AlkB oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in vitro.
- Authors: Bian K, Lenz SAP, Tang Q, Chen F, Qi R, Jost M, Drennan CL, Essigmann JM, Wetmore SD, Li D
- Issue date: 2019 Jun 20
- Protein expression and methylation of MGMT, a DNA repair gene and their correlation with clinicopathological parameters in invasive ductal carcinoma of the breast.
- Authors: Asiaf A, Ahmad ST, Malik AA, Aziz SA, Rasool Z, Masood A, Zargar MA
- Issue date: 2015 Aug
- Simultaneous CXCL12 and ESR1 CpG island hypermethylation correlates with poor prognosis in sporadic breast cancer.
- Authors: Ramos EA, Camargo AA, Braun K, Slowik R, Cavalli IJ, Ribeiro EM, Pedrosa Fde O, de Souza EM, Costa FF, Klassen G
- Issue date: 2010 Jan 28
- Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation.
- Authors: Rauscher GH, Kresovich JK, Poulin M, Yan L, Macias V, Mahmoud AM, Al-Alem U, Kajdacsy-Balla A, Wiley EL, Tonetti D, Ehrlich M
- Issue date: 2015 Oct 29
- DNA methylation mediated silencing of microRNA-874 is a promising diagnosis and prognostic marker in breast cancer.
- Authors: Zhang L, Yan DL, Yang F, Wang DD, Chen X, Wu JZ, Tang JH, Xia WJ
- Issue date: 2017 Jul 11