Accelerated aging in normal breast tissue of women with breast cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34022936", "kind": "science-record", "revision": 7, "content_hash": "sha256:a102cf6734ffa9c8cdbd5a744acd1f03a39e8a91aeb7d81d021e05798790c473", "created_at": "2026-11-01T15:41:36Z", "updated_at": "2026-11-01T22:03:48Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Accelerated aging in normal breast tissue of women with breast cancer.", "doi": "10.1186/s13058-021-01434-7", "pmid": "34022936", "authors": ["Shoghag Panjarian", "Jozef Madzo", "Kelsey Keith", "Carolyn M Slater", "Carmen Sapienza", "Jaroslav Jelinek", "Jean-Pierre J Issa"], "journal": "Breast cancer research : BCR", "year": 2021, "abstract": "BACKGROUND: DNA methylation alterations have similar patterns in normal aging tissue and in cancer. In this study, we investigated breast tissue-specific age-related DNA methylation alterations and used those methylation sites to identify individuals with outlier phenotypes. Outlier phenotype is identified by unsupervised anomaly detection algorithms and is defined by individuals who have normal tissue age-dependent DNA methylation levels that vary dramatically from the population mean.\nMETHODS: We generated whole-genome DNA methylation profiles (GSE160233) on purified epithelial cells and used publicly available Infinium HumanMethylation 450K array datasets (TCGA, GSE88883, GSE69914, GSE101961, and GSE74214) for discovery and validation.\nRESULTS: We found that hypermethylation in normal breast tissue is the best predictor of hypermethylation in cancer. Using unsupervised anomaly detection approaches, we found that about 10% of the individuals (39/427) were outliers for DNA methylation from 6 DNA methylation datasets. We also found that there were significantly more outlier samples in normal-adjacent to cancer (24/139, 17.3%) than in normal samples (15/228, 5.2%). Additionally, we found significant differences between the predicted ages based on DNA methylation and the chronological ages among outliers and not-outliers. Additionally, we found that accelerated outliers (older predicted age) were more frequent in normal-adjacent to cancer (14/17, 82%) compared to normal samples from individuals without cancer (3/17, 18%). Furthermore, in matched samples, we found that the epigenome of the outliers in the pre-malignant tissue was as severely altered as in cancer.\nCONCLUSIONS: A subset of patients with breast cancer has severely altered epigenomes which are characterized by accelerated aging in their normal-appearing tissue. In the future, these DNA methylation sites should be studied further such as in cell-free DNA to determine their potential use as biomarkers for early detection of malignant transformation and preventive intervention in breast cancer.", "claims": [{"id": "claim-method", "statement": "Next, we calculated an unsupervised anomaly detection parameter, the local outlier factor (LOF) on all the principal components of PCA using the DMwR and Rlof packages in R [29, 30].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34022936", "locator": "sections[7] \"Identification of outlier samples and age prediction\" paragraph 2", "quote": "Next, we calculated an unsupervised anomaly detection parameter, the local outlier factor (LOF) on all the principal components of PCA using the DMwR and Rlof packages in R [29, 30]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The dataset generated and analyzed during the current study is available from the corresponding author on request. In addition, the DNA methylation profiles discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus database under accession number GSE160233.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34022936", "locator": "sections[25] \"Availability of data and materials\" paragraph 2", "quote": "The dataset generated and analyzed during the current study is available from the corresponding author on request. In addition, the DNA methylation profiles discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus database under accession number GSE160233."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": null, "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:34022936"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE101961"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "blocked", "blocked_on": "method:group_comparison_wilcoxon", "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE101961"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:run_analysis blocked on method:group_comparison_wilcoxon"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34022936", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s13058-021-01434-7", "sha256": "sha256:fb518b0bec6bec05e05479f7e3d0c2a3d1b096a1dc5d829f87550ce88bb4af3d", "bytes": 64461, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s13058-021-01434-7", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8140515", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE101961", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101961", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE101961", "version": null, "note": "The dataset generated and analyzed during the current study is available from the corresponding author on request. In addition, the DNA methylation profiles discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus database under accession number GSE160233.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The dataset generated and analyzed during the current study is available from the corresponding author on request. 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407, "group_sizes": null, "group_sizes_basis": null, "platform": "16304", "taxon": "Homo sapiens", "title": "Genome wide DNA methylation profiling of normal breast, normal adjacent and breast cancer tissue", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE74214", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE74214", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE74214", "version": null, "note": "The dataset generated and analyzed during the current study is available from the corresponding author on request. In addition, the DNA methylation profiles discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus database under accession number GSE160233.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The dataset generated and analyzed during the current study is available from the corresponding author on request. 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