| Title |
CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer
|
|---|---|
| Published in |
BMC Cancer, July 2017
|
| DOI | 10.1186/s12885-017-3453-8 |
| Pubmed ID | |
| Authors |
Olafur Andri Stefansson, Stefan Hermanowicz, Jasper van der Horst, Holmfridur Hilmarsdottir, Zuzanna Staszczak, Jon Gunnlaugur Jonasson, Laufey Tryggvadottir, Thorkell Gudjonsson, Stefan Sigurdsson |
| Abstract |
DNA 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. |
Mendeley readers
The data shown below were compiled from readership statistics for 33 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 33 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 7 | 21% |
| Student > Ph. D. Student | 7 | 21% |
| Student > Master | 4 | 12% |
| Professor > Associate Professor | 4 | 12% |
| Researcher | 1 | 3% |
| Other | 1 | 3% |
| Unknown | 9 | 27% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 11 | 33% |
| Agricultural and Biological Sciences | 7 | 21% |
| Medicine and Dentistry | 3 | 9% |
| Pharmacology, Toxicology and Pharmaceutical Science | 1 | 3% |
| Environmental Science | 1 | 3% |
| Other | 1 | 3% |
| Unknown | 9 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 July 2017.
All research outputs
#20,434,884
of 22,988,380 outputs
Outputs from BMC Cancer
#6,527
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Outputs of similar age
#273,184
of 313,312 outputs
Outputs of similar age from BMC Cancer
#103
of 123 outputs
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