CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:28679371", "kind": "science-record", "revision": 7, "content_hash": "sha256:4a053e3d9158ae745b9a0d657cc75d6279ce3a233f0985f44bfdd2d1aafaf72f", "created_at": "2026-11-01T15:40:27Z", "updated_at": "2026-11-01T21:59:26Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.", "doi": "10.1186/s12885-017-3453-8", "pmid": "28679371", "authors": ["Olafur Andri Stefansson", "Stefan Hermanowicz", "Jasper van der Horst", "Holmfridur Hilmarsdottir", "Zuzanna Staszczak", "Jon Gunnlaugur Jonasson", "Laufey Tryggvadottir", "Thorkell Gudjonsson", "Stefan Sigurdsson"], "journal": "BMC cancer", "year": 2017, "abstract": "BACKGROUND: 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.\nMETHODS: 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.\nRESULTS: 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).\nCONCLUSIONS: 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.", "claims": [{"id": "claim-method", "statement": "The P-value shown was derived from Spearman’s correlation testing (Spearman’s rho = −0.577; P = 0.024)", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:28679371", "locator": "sections[13] \"CpG promoter methylation and expression of the ALKBH3 gene in normal and primary breast tumor samples\" paragraph 3", "quote": "The P-value shown was derived from Spearman’s correlation testing (Spearman’s rho = −0.577; P = 0.024)"}], "state": "complete"}, {"id": "claim-data-access", "statement": "Methylome datasets used in this study: Stefansson et al. (GSE52865), Dedeurwaerder et al. (GSE20713) and Teschendorff et al. (GSE69914).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:28679371", "locator": "sections[25] \"Availability of data and materials\" paragraph 2", "quote": "Methylome datasets used in this study: Stefansson et al. (GSE52865), Dedeurwaerder et al. (GSE20713) and Teschendorff et al. (GSE69914)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Using CpG promoter methylation analyses of Omnibus methylome datasets GSE52865, GSE20713, and GSE69914, complemented by TCGA expression data and pyrosequencing, the study found that ALKBH3—but not ALKBH2—undergoes promoter methylation and transcriptional silencing in breast cancer.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:28679371", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Methylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation."}, {"asset": "source:pmid:28679371", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3."}, {"asset": "source:pmid:28679371", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "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."}, {"asset": "source:pmid:28679371", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "The ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Using CpG promoter methylation analyses of Omnibus methylome datasets GSE52865, GSE20713, and GSE69914, complemented by TCGA expression data and pyrosequencing, the study found that ALKBH3—but not ALKBH2—undergoes promoter methylation and transcriptional silencing in breast cancer.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:28679371"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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"Positive", "Negative", "", ""], ["Estrogen-Receptor", "175 (72%)", "68 (28%)", "", ""], ["Progestrone-Receptor", "136 (56%)", "108 (44%)", "", ""], ["HER2-positive (over-expressed)", "20 (14%)", "121 (86%)", "", ""], ["Ki67-positive (>14% positivity)", "84 (60%)", "55 (40%)", "", ""], ["", "1986–1991", "1991–1996", "1996–2001", "2001–2004"], ["Year of Diagnosis", "81 (30%)", "121 (46%)", "60 (23%)", "3 (1%)"], ["", "26–42", "42–58", "58–74", "74–91"], ["Age at Diagnosis", "36 (14%)", "104 (39%)", "80 (30%)", "45 (17%)"], ["", "5–30", "30–55", "55–80", "80–100"], ["Tumour size (mm)", "94 (77%)", "24 (20%)", "1 (1%)", "3 (2%)"], ["Nodal status", "112 (64%)", "63 (36%)", "", ""], ["", "+", "++", "+++", ""], ["Histological Grade", "19 (13%)", "62 (41%)", "69 (46%)", ""]], "row_count": 14, "column_count": 5, "numeric_cells": 38, "header_rows": 1, "locator": "section[14]/table-wrap[1]#Tab1"}}], "gaps": ["asset:data:geo:GSE20713 not downloaded", "asset:data:geo:GSE20713 licence not read", 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DNA alkylation damage assay w"], "order_basis": "paper_text_order:1068", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical param", "itative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels", "3 analysed with respect to 3-methyl-cytosine immunostaining. A) U2OS cells were transfected with a contr", "(to gain access to single stranded DNA) and immunostained for 3-me-C and 5-me-C. As expected, decrease"], "order_basis": "paper_text_order:1167", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["pect to 3-methyl-cytosine immunostaining. A) U2OS cells were transfected with a control (scram"], "order_basis": "paper_text_order:6318", "id": "assay:3"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["-cytosine immunostaining. A) U2OS cells were transfected with a control (scrambled siRNA) and ALKBH3", "s were transfected with a control (scrambled siRNA) and ALKBH3 siRNA for 72 h. 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