Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:29682089", "kind": "science-record", "revision": 7, "content_hash": "sha256:0501b4e4d4b2f4ed09bfc4ecbef9e5cf9b8812437bff64644df8e0a87b8ff4d6", "created_at": "2026-11-01T15:40:33Z", "updated_at": "2026-11-01T21:59:48Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer.", "doi": "10.1186/s13148-018-0479-y", "pmid": "29682089", "authors": ["Lieselot Croes", "Matthias Beyens", "Erik Fransen", "Joe Ibrahim", "Wim Vanden Berghe", "Arvid Suls", "Marc Peeters", "Patrick Pauwels", "Guy Van Camp", "Ken Op de Beeck"], "journal": "Clinical epigenetics", "year": 2018, "abstract": "Background: Breast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. We hypothesized that deafness, autosomal dominant 5 (DFNA5) may be a valuable biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death. In this study, we aimed to analyze DFNA5 methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of DFNA5 as detection and/or prognostic marker in breast cancer. We analyzed Infinium HumanMethylation450k data, covering 22 different CpGs in the DFNA5 gene (668 breast adenocarcinomas and 85 normal breast samples) and DFNA5 expression (Agilent 244K Custom Gene Expression: 476 breast adenocarcinomas and 56 normal breast samples; RNA-sequencing: 666 breast adenocarcinomas and 71 normal breast samples).\nResults: DFNA5 methylation and expression were significantly different between breast cancer and normal breast samples. Overall, breast cancer samples showed higher DFNA5 methylation in the putative gene promoter compared to normal breast samples, whereas in the gene body and upstream of the putative gene promoter, the opposite is true. Furthermore, DFNA5 methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5, which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93). This model was externally validated in three independent datasets. Moreover, we showed that estrogen receptor state is associated with DFNA5 methylation and expression. Finally, we were able to find a significant effect of DFNA5 gene body methylation on a 5-year overall survival time.\nConclusions: We conclude that DFNA5 methylation shows strong potential as detection and prognostic biomarker for breast cancer.", "claims": [{"id": "claim-method", "statement": "Cox proportional hazard models were fit using the survival package [42], to model 5-year overall survival (OS) time based upon either DFNA5 methylation or DFNA5 expression (microarray or RNA-seq), accounting for age.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29682089", "locator": "sections[8] \"Statistical analysis\" paragraph 4", "quote": "Cox proportional hazard models were fit using the survival package [42], to model 5-year overall survival (OS) time based upon either DFNA5 methylation or DFNA5 expression (microarray or RNA-seq), accounting for age."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets analyzed during the current study are available in the following open access repositories:TCGA, https://cancergenome.nih.gov/GEO, https://www.ncbi.nlm.nih.gov/geo/ (GEO accession numbers: GSE52865, GSE69914 and GSE60185)miRTarBase, http://mirtarbase.mbc.nctu.edu.tw/index.php.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:29682089", "locator": "sections[23] \"ack\" paragraph 1", "quote": "The datasets analyzed during the current study are available in the following open access repositories:TCGA, https://cancergenome.nih.gov/GEO, https://www.ncbi.nlm.nih.gov/geo/ (GEO accession numbers: GSE52865, GSE69914 and GSE60185)miRTarBase, http://mirtarbase.mbc.nctu.edu.tw/index.php."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Using publicly available TCGA data and linear mixed models that accounted for batch effects, the study found that a two-CpG DFNA5 methylation model discriminated breast adenocarcinoma from normal breast samples with an AUC of 0.93 and was externally validated in three independent datasets.", "kind": "quantitative", "target": {"value": 0.93, "unit": "auc", "tolerance": null, "source": "An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5, which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93)."}, "evidence": [{"asset": "source:pmid:29682089", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "In this study, we aimed to analyze DFNA5 methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of DFNA5 as detection and/or prognostic marker in breast cancer."}, {"asset": "source:pmid:29682089", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of DFNA5, which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93)."}, {"asset": "source:pmid:29682089", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "This model was externally validated in three independent datasets."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Using publicly available TCGA data and linear mixed models that accounted for batch effects, the study found that a two-CpG DFNA5 methylation model discriminated breast adenocarcinoma from normal breast samples with an AUC of 0.93 and was externally validated in three independent datasets.", "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:29682089"], "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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https://cancergenome.nih.gov/GEO, https://www.ncbi.nlm.nih.gov/geo/ (GEO accession numbers: GSE52865, GSE69914 and GSE60185)miRTarBase, http://mirtarbase.mbc.nctu.edu.tw/index.php.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The datasets analyzed during the current study are available in the following open access repositories:TCGA, https://cancergenome.nih.gov/GEO, https://www.ncbi.nlm.nih.gov/geo/ (GEO accession numbers: GSE52865, GSE69914 and GSE60185)miRTarBase, http://mirtarbase.mbc.nctu.edu.tw/index.php.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1277199", "GSM1277200", "GSM1277201", "GSM1277202", "GSM1277203", "GSM1277204", "GSM1277205", "GSM1277206", "GSM1277207", "GSM1277208", "GSM1277209", "GSM1277210", "GSM1277211", "GSM1277212", "GSM1277213", "GSM1277214", "GSM1277215", "GSM1277216", "GSM1277217", "GSM1277218", "GSM1277219", "GSM1277220", "GSM1277221", "GSM1277222", 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(15/22 CpGs)", "", "N.S.", "", "N.S."], ["PR+", "428 (64.1)", "", "310 (65.1)", "", "427 (64.1)", ""], ["PR−", "201 (30.1)", "", "158 (33.2)", "", "200 (30.0)", ""], ["Unknown", "39 (5.8)", "", "8 (1.7)", "", "39 (5.9)", ""], ["HER2", "", "0.023 (1/22 CpGs)", "", "N.S.", "", "N.S."], ["HER2+", "32 (4.8)", "", "45 (9.4)", "", "32 (4.8)", ""], ["HER2−", "195 (29.2)", "", "166 (34.9)", "", "195 (29.3)", ""], ["Unknown", "441 (66.0)", "", "265 (55.7)", "", "439 (65.9)", ""], ["Tumor stage", "", "1.9 × 10−4–0.020 (5/22 CpGs)", "", "N.S.", "", "N.S."], ["I", "109 (16.3)", "", "83 (17.5)", "", "107 (16.1)", ""], ["II", "378 (56.6)", "", "269 (56.5)", "", "378 (56.8)", ""], ["III", "166 (24.9)", "", "99 (20.8)", "", "166 (24.9)", ""], ["IV", "9 (1.3)", "", "12 (2.5)", "", "9 (1.3)", ""], ["Unknown", "6 (0.9)", "", "13 (2.7)", "", "6 (0.9)", ""], ["Histological diagnosis", "", "1.0 × 10−4–0.038 (10/22 CpGs)", "", "4.2 × 10−4", "", "3.2 × 10−4"], ["Ductal", "496 (74.3)", "", "435 (91.4)", "", "494 (74.2)", ""], ["Lobular", "172 (25.7)", "", "41 (8.6)", "", "172 (25.8)", ""]], "row_count": 23, "column_count": 7, "numeric_cells": 60, "header_rows": 2, "locator": "section[3]/table-wrap[1]#Tab1"}}, {"id": "asset:table:pmid:29682089:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:cddc5c0cb6a2bdcd2317f657c8b8792be1f3579ede6fb1c5d425e19a88444887", "bytes": 2509, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#Tab2", "version": null, "note": "The effect of methylation of every of the 22 CpGs on 5-year OS time", "structure": {"pmcid": "PMC5896072", "section_index": 16, "section_title": "Associations between DFNA5 methylation or expression and 5-year overall survival", "row_count": 24, "column_count": 11}, "table": {"label": "Table 2", "caption": "The effect of methylation of every of the 22 CpGs on 5-year OS time", "rows": [["CpG", "Genomic coordinate (GRCh37)", "All breast adenocarcinomas", "Ductal adenocarcinomas", "Lobular adenocarcinomas"], ["Regression coefficient", "S.E.", "P value", "Regression coefficient", "S.E.", "P value", "Regression coefficient", "S.E.", "P value"], ["CpG17790129", "24738572", "5.1", "1.9", "8.2 × 10−3 *", "6.0", "2.5", "0.019 *", "2.3", "3.8", "0.54"], ["CpG14205998", "24748668", "5.1", "2.1", "0.015 *", "4.9", "2.1", "0.023 *", "13.9", "11.9", "0.24"], ["CpG04317854", "24762562", "1.8", "1.3", "0.16", "2.6", "1.4", "0.064", "− 2.6", "3.5", "0.46"], ["CpG12922093", "24767644", "3.1", "1.2", "0.012 *", "3.8", "1.4", "6.2 × 10−3 *", "− 1.9", "4.2", "0.66"], ["CpG17569154", "24781545", "3.0", "1.2", "0.012 *", "3.6", "1.3", "6.3 × 10−3 *", "− 2.3", "4.4", "0.61"], ["CpG19260663", "24791121", "5.3", "1.9", "4.2 × 10−3 *", "5.7", "2.0", "5.5 × 10−3 *", "7.5", "6.3", "0.23"], ["CpG09333471", "24796355", "2.5", "1.3", "0.059", "1.7", "1.4", "0.22", "11.4", "6.8", "0.093"], ["CpG00473134", "24796494", "0.81", "1.4", "0.57", "0.78", "1.6", "0.62", "4.3", "4.8", "0.37"], ["CpG03995857", "24796553", "− 0.19", "1.0", "0.85", "− 0.75", "1.1", "0.49", "7.4", "5.2", "0.16"], ["CpG07320646", "24796981", "− 0.49", "0.84", "0.55", "− 1.3", "1.0", "0.22", "7.0", "5.3", "0.19"], ["CpG07293520", "24797192", "− 0.17", "1.2", "0.89", "− 1.7", "1.6", "0.29", "9.5", "5.3", "0.072"], ["CpG04770504", "24797363", "− 1.3", "1.2", "0.27", "− 2.4", "1.4", "0.098", "11.7", "8.8", "0.18"], ["CpG24805239", "24797486", "− 0.19", "1.2", "0.87", "− 0.91", "1.3", "0.49", "6.4", "4.5", "0.16"], ["CpG01733570", "24797656", "0.97", "1.0", "0.34", "0.77", "1.0", "0.44", "3.9", "3.9", "0.32"], ["CpG25723149", "24797680", "0.14", "1.0", "0.89", "0.18", "1.0", "0.86", "2.2", "4.1", "0.59"], ["CpG22804000", "24797691", "− 0.092", "1.1", "0.93", "0.087", "1.1", "0.94", "0.51", "3.9", "0.90"], ["CpG07504598", "24797786", "− 0.31", "1.1", "0.77", "− 0.13", "1.1", "0.91", "0.87", "4.2", "0.83"], 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