{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:17:14Z","timestamp":1777868234669,"version":"3.51.4"},"reference-count":80,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Despite major advances in early breast cancer detection and therapeutic strategies, locoregional and distant recurrences, as well as the development of a second primary breast cancer, remain major clinical challenges. Current prognostic tools primarily rely on tumor-specific features, such as the histological grade, hormone receptor status, and proliferative index, and, more recently, on molecular signatures aimed at improving risk stratification and predicting recurrence. However, these approaches remain imperfect, and there is an urgent need to develop complementary strategies. Growing attention has been focused on the tumor microenvironment and the surrounding non-tumoral tissue, which may harbor clinically relevant molecular alterations. Emerging evidence suggests that DNA methylation changes can be detected in the adjacent and contralateral breast tissue and reflect early steps of carcinogenesis or predisposition to tumor development. This phenomenon, often referred to as field cancerization, raises new questions about the dynamics of cancer development. The aim of this work is to provide an integrative overview of DNA methylation alterations in normal breast tissue, including peritumoral and contralateral areas, and to examine their potential as predictive biomarkers of recurrence, based on the available data from tumoral tissue. In theory, these applications seem promising, but their role needs to be confirmed in large prospective trials, in order to overcome barriers to clinical implementation. The currently available evidence does not support a role for DNA methylation in the selection of locoregional and systemic treatment strategies, particularly with a view to reducing the rising number of uni- and bilateral mastectomies performed without any demonstrated survival benefit.<\/jats:p>","DOI":"10.3390\/cimb48050466","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:47:28Z","timestamp":1777546048000},"page":"466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Can DNA Methylation in Peritumoral and Contralateral Breast Tissue Predict Recurrence or Second Breast Cancers?"],"prefix":"10.3390","volume":"48","author":[{"given":"Jennifer","family":"Hammer","sequence":"first","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Malvaux","sequence":"additional","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"van Drooghenbroeck","sequence":"additional","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9dric","family":"Van Marcke","sequence":"additional","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5429-7888","authenticated-orcid":false,"given":"Francois P.","family":"Duhoux","sequence":"additional","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-9867","authenticated-orcid":false,"given":"Martine","family":"Berliere","sequence":"additional","affiliation":[{"name":"Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint Luc, Universit\u00e9 Catholique de Louvain, 1200 Woluwe-Saint-Lambert, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer. J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.4103\/ijc.IJC_178_17","article-title":"Predicting loco-regional recurrence risk in T1, T2 breast cancer with 1\u20133 positive axillary nodes postmastectomy: Development of a predictive nomogram","volume":"54","author":"Wadasadawala","year":"2017","journal-title":"Indian. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.breast.2018.03.011","article-title":"Incidence of isolated local breast cancer recurrence and contralateral breast cancer: A systematic review","volume":"39","author":"Spronk","year":"2018","journal-title":"Breast"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Xiong, Z., Yang, L., Deng, G., Huang, X., Li, X., Xie, X., Wang, J., Shuang, Z., and Wang, X. (2018). Patterns of Occurrence and Outcomes of Contralateral Breast Cancer: Analysis of SEER Data. J. Clin. Med., 7.","DOI":"10.3390\/jcm7060133"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s10549-023-07071-2","article-title":"Ipsilateral breast tumor recurrence after breast-conserving surgery: Insights into biology and treatment","volume":"202","author":"Qu","year":"2023","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1200\/JCO.22.02553","article-title":"Local Recurrence After Breast-Conserving Therapy in Patients with Multiple Ipsilateral Breast Cancer: Results from ACOSOG Z11102 (Alliance)","volume":"41","author":"Boughey","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jama.2018.19323","article-title":"Breast Cancer Treatment: A Review","volume":"321","author":"Waks","year":"2019","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s10549-024-07338-2","article-title":"Risk of first recurrence after treatment in a population-based cohort of young women with breast cancer","volume":"206","author":"Schaffar","year":"2024","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1158\/1078-0432.CCR-08-2644","article-title":"Local recurrence after breast-conserving therapy in relation to gene expression patterns in a large series of patients","volume":"15","author":"Kreike","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/415530a","article-title":"Gene expression profiling predicts clinical outcome of breast cancer","volume":"415","author":"Dai","year":"2002","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s10549-022-06580-w","article-title":"Value of the 21-gene expression assay in predicting locoregional recurrence rates in estrogen receptor-positive breast cancer: A systematic review and network meta-analysis","volume":"193","author":"Davey","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1056\/NEJMoa041588","article-title":"A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer","volume":"351","author":"Paik","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/path.4847","article-title":"The molecular basis of breast cancer pathological phenotypes","volume":"241","author":"Heng","year":"2017","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10549-020-05611-8","article-title":"Prediction of contralateral breast cancer: External validation of risk calculators in 20 international cohorts","volume":"181","author":"Giardiello","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_15","first-page":"363","article-title":"Applying competing risks analysis to recurrences of primary breast cancer","volume":"47","author":"Mancini","year":"2023","journal-title":"Epidemiol. Prev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10549-016-4039-x","article-title":"A model for individualized risk prediction of contralateral breast cancer","volume":"161","author":"Chowdhury","year":"2017","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1097\/SLA.0000000000001698","article-title":"Growing Use of Contralateral Prophylactic Mastectomy Despite No Improvement in Long-term Survival for Invasive Breast Cancer","volume":"265","author":"Wong","year":"2017","journal-title":"Ann. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.breast.2021.02.003","article-title":"Contralateral prophylactic mastectomy: A narrative review of the evidence and acceptability","volume":"56","author":"Scheepens","year":"2021","journal-title":"Breast"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/14737140.2020.1732213","article-title":"Contralateral prophylactic mastectomy in breast cancer: What to discuss with patients","volume":"20","author":"Giardiello","year":"2020","journal-title":"Expert Rev. Anticancer. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1200\/JCO.20.02239","article-title":"Addressing the Dilemma of Contralateral Prophylactic Mastectomy With Behavioral Science","volume":"39","author":"Sacks","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13058-021-01434-7","article-title":"Accelerated aging in normal breast tissue of women with breast cancer","volume":"23","author":"Panjarian","year":"2021","journal-title":"Breast Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/sj.bjc.6605576","article-title":"Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile","volume":"102","author":"Graham","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S146239940200491X","article-title":"Breast cancer gene discovery","volume":"4","author":"Polyak","year":"2002","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10549-008-0165-4","article-title":"Genomic instability demonstrates similarity between DCIS and invasive carcinomas","volume":"117","author":"Heaphy","year":"2009","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q","article-title":"Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin","volume":"6","author":"Slaughter","year":"1953","journal-title":"Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Martisova, A., Holcakova, J., Izadi, N., Sebuyoya, R., Hrstka, R., and Bartosik, M. (2021). DNA Methylation in Solid Tumors: Functions and Methods of Detection. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084247"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chen, X., Zhang, J., and Dai, X. (2019). DNA methylation profiles capturing breast cancer heterogeneity. BMC Genom., 20.","DOI":"10.1186\/s12864-019-6142-y"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13148-023-01465-1","article-title":"DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer","volume":"15","author":"Koka","year":"2023","journal-title":"Clin. Epigenet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.molonc.2010.04.002","article-title":"The epigenetics of breast cancer","volume":"4","author":"Jovanovic","year":"2010","journal-title":"Mol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/path.5902","article-title":"Field cancerization in breast cancer","volume":"257","author":"Gadaleta","year":"2022","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13058-025-02057-y","article-title":"DNA methylation patterns in breast cancer, paired benign tissue from ipsilateral and contralateral breast, and healthy controls","volume":"27","author":"Dennis","year":"2025","journal-title":"Breast Cancer Res."},{"key":"ref_32","first-page":"CD013091","article-title":"Mammographic density, endocrine therapy and breast cancer risk: A prognostic and predictive biomarker review","volume":"10","author":"Atakpa","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Moura, T., Laranjeira, P., Caramelo, O., Gil, A.M., and Paiva, A. (2025). Breast Cancer and Tumor Microenvironment: The Crucial Role of Immune Cells. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32030143"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1093\/jnci\/djaf070","article-title":"Unraveling the role of stromal disruption in aggressive breast cancer etiology and outcomes","volume":"117","author":"Abubakar","year":"2025","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.7150\/ijbs.108803","article-title":"Unraveling the breast cancer tumor microenvironment: Crucial factors influencing natural killer cell function and therapeutic strategies","volume":"21","author":"Li","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1038\/s41467-018-05467-z","article-title":"Evaluating intrinsic and non-intrinsic cancer risk factors","volume":"9","author":"Wu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1475-2867-7-2","article-title":"Clinical implications and utility of field cancerization","volume":"7","author":"Dakubo","year":"2007","journal-title":"Cancer Cell. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"a019505","DOI":"10.1101\/cshperspect.a019505","article-title":"Epigenetic Determinants of Cancer","volume":"8","author":"Baylin","year":"2016","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"603","DOI":"10.21873\/cdp.10149","article-title":"Epigenetic Mechanisms in Breast Adenocarcinoma: Novel DNA Methylation Patterns","volume":"2","author":"Metaxas","year":"2022","journal-title":"Cancer Diagn. Progn."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1101\/gr.125872.111","article-title":"Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer","volume":"22","author":"Hon","year":"2012","journal-title":"Genome Res."},{"key":"ref_44","first-page":"435","article-title":"Genome-wide DNA methylation profiles in progression to in situand invasive carcinoma of the breast with impact on gene transcription and prognosis","volume":"15","author":"Fleischer","year":"2014","journal-title":"Genome Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/ng1941","article-title":"Epigenetic stem cell signature in cancer","volume":"39","author":"Widschwendter","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1002\/1878-0261.12309","article-title":"Specific breast cancer prognosis-subtype distinctions based onDNAmethylation patterns","volume":"12","author":"Zhang","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1200\/JCO.2008.18.1370","article-title":"Supervised risk predictor of breast cancer based on intrinsic subtypes","volume":"27","author":"Parker","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13148-021-01096-4","article-title":"NEFM DNA methylation correlates with immune infiltration and survival in breast cancer","volume":"13","author":"Li","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1080\/15592294.2020.1777666","article-title":"Association ofSOD3 promoter DNA methylation with its down-regulation in breast carcinomas","volume":"15","author":"Griess","year":"2020","journal-title":"Epigenetics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e19345","DOI":"10.1097\/MD.0000000000019345","article-title":"The association between the methylation frequency of BRCA1\/2 gene promoter and occurrence and prognosis of breast carcinoma: A meta-analysis","volume":"99","author":"Li","year":"2020","journal-title":"Medicine"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s13148-024-01787-8","article-title":"BRCA1 & BRCA2 methylation as a prognostic and predictive biomarker in cancer: Implementation in liquid biopsy in the era of precision medicine","volume":"16","author":"Panagopoulou","year":"2024","journal-title":"Clin. Epigenet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1056\/NEJMoa1804710","article-title":"Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer","volume":"379","author":"Sparano","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S1470-2045(21)00007-3","article-title":"70-gene signature as an aid for treatment decisions in early breast cancer: Updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age","volume":"22","author":"Piccart","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ren, J.-T., Wang, M.-X., Su, Y., Tang, L.-Y., and Ren, Z.-F. (2018). Decelerated DNA methylation age predicts poor prognosis of breast cancer. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4884-6"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s10549-019-05417-3","article-title":"CpG methylation signature predicts prognosis in breast cancer","volume":"178","author":"Du","year":"2019","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1002\/jcb.29461","article-title":"A seven-DNA methylation signature as a novel prognostic biomarker in breast cancer","volume":"121","author":"Tao","year":"2020","journal-title":"J. Cell. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Liu, X.-P., Hou, J., Chen, C., Guan, L., Hu, H.-K., and Li, S. (2020). A DNA Methylation-Based Panel for the Prognosis and Dagnosis of Patients with Breast Cancer and Its Mechanisms. Front. Mol. Biosci., 7, Erratum in: Front. Mol. Biosci. 2020, 7, 596445.","DOI":"10.3389\/fmolb.2020.00118"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41523-020-0145-3","article-title":"DNA methylation markers predict recurrence-free interval in triple-negative breast cancer","volume":"6","author":"Fackler","year":"2020","journal-title":"NPJ Breast Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13058-022-01537-9","article-title":"DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival","volume":"24","author":"Pedersen","year":"2022","journal-title":"Breast Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9378","DOI":"10.1111\/jcmm.15588","article-title":"Development and validation of a novel 15-CpG-based signature for predicting prognosis in triple-negative breast cancer","volume":"24","author":"Peng","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13058-024-01955-x","article-title":"Tumour DNA methylation markers associated with breast cancer survival: A replication study","volume":"27","author":"Zarean","year":"2025","journal-title":"Breast Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7414","DOI":"10.1073\/pnas.1703577114","article-title":"DNA methylation markers for diagnosis and prognosis of common cancers","volume":"114","author":"Hao","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1158\/1541-7786.MCR-10-0424","article-title":"Breast Field Cancerization: Isolation and Comparison of Telomerase-Expressing Cells in Tumor and Tumor Adjacent, Histologically Normal Breast Tissue","volume":"9","author":"Trujillo","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13058-017-0873-y","article-title":"Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age","volume":"19","author":"Johnson","year":"2017","journal-title":"Breast Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1158\/1055-9965.EPI-22-0405","article-title":"Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer-Risk Factors","volume":"32","author":"Muse","year":"2023","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10478","DOI":"10.1038\/ncomms10478","article-title":"DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer","volume":"7","author":"Teschendorff","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"9533461","DOI":"10.1155\/2022\/9533461","article-title":"Evaluating DNA Methylation in Random Fine Needle Aspirates from the Breast to Inform Cancer Risk","volume":"2022","author":"Visvanathan","year":"2022","journal-title":"Breast J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"868","DOI":"10.4161\/epi.20830","article-title":"Global DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry","volume":"7","author":"Wu","year":"2012","journal-title":"Epigenetics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1093\/carcin\/bgs201","article-title":"Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry","volume":"33","author":"Wu","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"03000605231220827","DOI":"10.1177\/03000605231220827","article-title":"Septin9 DNA methylation is associated with breast cancer recurrence or metastasis","volume":"52","author":"Zhang","year":"2024","journal-title":"J. Int. Med. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ebiom.2018.04.025","article-title":"DNA Methylation Patterns in Normal Tissue Correlate more Strongly with Breast Cancer Status than Copy-Number Variants","volume":"31","author":"Gao","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Avraham, A., Cho, S.S., Uhlmann, R., Polak, M.L., Sandbank, J., Karni, T., Pappo, I., Halperin, R., Vaknin, Z., and Sella, A. (2014). Tissue specific DNA methylation in normal human breast epithelium and in breast cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091805"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13148-022-01239-1","article-title":"Aberrant epigenetic and transcriptional events associated with breast cancer risk","volume":"14","author":"Marino","year":"2022","journal-title":"Clin. Epigenet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13148-018-0534-8","article-title":"Increased epigenetic age in normal breast tissue from luminal breast cancer patients","volume":"10","author":"Hofstatter","year":"2018","journal-title":"Clin. Epigenet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/s43587-021-00104-9","article-title":"Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations","volume":"1","author":"Shalabi","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/CCO.0000000000000152","article-title":"How the environment shapes cancer genomes","volume":"27","author":"Pfeifer","year":"2015","journal-title":"Curr. Opin. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41576-024-00748-4","article-title":"Methods and applications of genome-wide profiling of DNA damage and rare mutations","volume":"25","author":"Pfeifer","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/onc.2016.192","article-title":"Base changes in tumour DNA have the power to reveal the causes and evolution of cancer","volume":"36","author":"Hollstein","year":"2017","journal-title":"Oncogene"},{"key":"ref_79","first-page":"186","article-title":"Mutually exclusive epigenetic modification on SIX6 with hypermethylation for precancerous stage and metastasis emergence tracing","volume":"7","author":"Dong","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1200\/JCO.2009.24.9284","article-title":"Breast cancer subtypes and the risk of local and regional relapse","volume":"28","author":"Voduc","year":"2010","journal-title":"J. Clin. Oncol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T11:38:59Z","timestamp":1777549139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":80,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cimb48050466"],"URL":"https:\/\/doi.org\/10.3390\/cimb48050466","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}