{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:36Z","timestamp":1785428076647,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004263","name":"Research Support Foundation of the State of Rio Grande do Sul","doi-asserted-by":"publisher","award":["12\/1926-9"],"award-info":[{"award-number":["12\/1926-9"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["479564\/2013-2"],"award-info":[{"award-number":["479564\/2013-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"award":["479564\/2013-2"],"award-info":[{"award-number":["479564\/2013-2"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"publisher"}]},{"name":"PPSUS- FAPERGS\/MS\/CNPq\/SESRS","award":["1313-2551\/13-8"],"award-info":[{"award-number":["1313-2551\/13-8"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Breast cancer is the most prevalent malignant disease among women. Here, we investigate whether there is an association between disease recurrence in breast cancer patients and the quantitative methylation pattern of seven genes of different DNA repair pathways. Methods: Clinical and pathological data from 30 patients treated for sporadic breast cancer were selected according to the following inclusion criteria: follow-up of 5 years, adjuvant chemotherapy and recurrence. Histopathology was verified, and genomic DNA was accessed by tumor cryosectioning. We also determined the methylation levels of seven DNA repair genes (BRCA1, BRCA2, XRCC1, PARP1, ERCC4, MGMT, and XPC). Results: Patients without recurrence demonstrated a higher index of positive progesterone receptor status compared to patients with recurrence (p = 0.025). All other clinical characteristics of the patients did not differ between the groups. BRCA1 and BRCA2 genes showed methylation, and there was a higher level of BRCA1 gene methylation in patients without recurrence. BRCA1 methylation was not associated with the clinical characteristics of patients. All other genes analyzed showed no difference in methylation between patients with and without recurrence. Conclusions: We showed that sporadic breast cancer patients with a lower incidence of recurrence demonstrate a higher level of BRCA1 gene methylation after 5 years of follow-up, suggesting its role as a predictive biomarker.<\/jats:p>","DOI":"10.3390\/medsci14020251","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:46:55Z","timestamp":1778676415000},"page":"251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Higher Levels of BRCA1 Gene Methylation in Sporadic Breast Cancer Patients with a Lower Incidence of Recurrence"],"prefix":"10.3390","volume":"14","author":[{"given":"Grasiela","family":"Agnes","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5246-7388","authenticated-orcid":false,"given":"Andrea Pires Souto","family":"Damin","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90035-903, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Watte","sequence":"additional","affiliation":[{"name":"Epidemiology, Department of Respiratory Medicine and Thoracic Surgery, Irmandade Santa Casa de Miseric\u00f3rdia de Porto Alegre, Porto Alegre 90020-090, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliano Rizzotto","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6294-7342","authenticated-orcid":false,"given":"Adriana Vial","family":"Roehe","sequence":"additional","affiliation":[{"name":"Department of Pathology and Legal Medicine, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5372-2934","authenticated-orcid":false,"given":"Jenifer","family":"Saffi","sequence":"additional","affiliation":[{"name":"Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Rua Sarmento Leite, 245, Porto Alegre 90050-170, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"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","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"de Oliveira Santos, M., de Lima, F.C.d.S., Martins, L.F.L., Oliveira, J.F.P., de Almeida, L.M., and de Camargo Cancela, M. (2023). Estimativa de incid\u00eancia de c\u00e2ncer no Brasil, 2023\u20132025. Rev. Bras. Cancerol., 69.","DOI":"10.32635\/2176-9745.RBC.2023v69n1.3700"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/gm325","article-title":"DNA methylation signatures for breast cancer classification and prognosis","volume":"4","author":"Szyf","year":"2012","journal-title":"Genome Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Turashvili, G., and Brogi, E. (2017). Tumor heterogeneity in breast cancer. Front. Med., 4.","DOI":"10.3389\/fmed.2017.00227"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37331","DOI":"10.18632\/oncotarget.7949","article-title":"The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer","volume":"7","author":"Gao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"329","DOI":"10.5306\/wjco.v2.i9.329","article-title":"DNA damage and breast cancer","volume":"2","author":"Davis","year":"2011","journal-title":"World J. Clin. Oncol."},{"key":"ref_8","first-page":"77","article-title":"DNA repair in cancer: Emerging targets for personalized therapy","volume":"6","author":"Abbotts","year":"2014","journal-title":"Cancer Manag. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/jmcb\/mjq053","article-title":"Epigenetic changes of DNA repair genes in cancer","volume":"3","author":"Lahtz","year":"2011","journal-title":"J. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.dnarep.2017.03.009","article-title":"DNA repair and damage pathways in breast cancer development and therapy","volume":"54","author":"Majidinia","year":"2017","journal-title":"DNA Repair"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrc.2015.21","article-title":"BRCAness revisited","volume":"16","author":"Lord","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mylavarapu, S., Das, A., and Roy, M. (2018). Role of BRCA mutations in the modulation of response to platinum therapy. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00016"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s10549-022-06774-2","article-title":"Methylation of promoter region of BRCA1 gene versus pathogenic variants of gene: Risk factor or clinical marker of breast cancer","volume":"196","author":"Lobanova","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13053-025-00317-8","article-title":"BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients","volume":"23","author":"Prajzendanc","year":"2025","journal-title":"Hered. Cancer Clin. Pract."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1038\/ng.3934","article-title":"A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer","volume":"49","author":"Polak","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1158\/2159-8290.CD-12-0462","article-title":"The genomic landscape of breast cancer as a therapeutic roadmap","volume":"3","author":"Ellis","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mrrev.2017.10.001","article-title":"Epigenetic regulation of DNA repair genes and implications for tumor therapy","volume":"780","author":"Christmann","year":"2019","journal-title":"Mutat. Res.\/Rev. Mutat. Res."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/modpathol.2012.214","article-title":"Molecular pathological epidemiology of epigenetics: Emerging integrative science to analyze environment, host, and disease","volume":"26","author":"Ogino","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_20","first-page":"4569","article-title":"The role of methylation in breast cancer susceptibility and treatment","volume":"35","author":"Pouliot","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11954","DOI":"10.1158\/0008-5472.CAN-06-1666","article-title":"Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant","volume":"66","author":"Fan","year":"2006","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4101","DOI":"10.1158\/0008-5472.CAN-05-0064","article-title":"Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer","volume":"65","author":"Martens","year":"2005","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1038\/s41467-018-03951-0","article-title":"Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1","volume":"9","author":"Zhu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.4161\/epi.22561","article-title":"BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer","volume":"7","author":"Stefansson","year":"2012","journal-title":"Epigenetics"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bacares, R., Soslow, R., Olvera, N., Levine, D.A., and Zhang, L. (2025). A Rapid and Reliable Test for BRCA1 Promoter Hypermethylation in Paraffin Tissue Using Pyrosequencing. Diagnostics, 15.","DOI":"10.3390\/diagnostics15050601"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Willmer, T., Makhetha, M., Shaik, A.R., Mabasa, L., Buccimazza, I., and Aldous, C. (2026). BRCA1 Promoter CpG Methylation in Breast Cancer: A Pilot Study in African Women. Genes, 17.","DOI":"10.3390\/genes17040407"},{"key":"ref_27","first-page":"2018","article-title":"EpiTect Methyl II PCR Array System: A simple tool for screening regional DNA methylation of a large number of genes or samples without bisulfite conversion","volume":"11","author":"Jiang","year":"2012","journal-title":"Qiagen, Valencia, CA. Accessed"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.pan.2021.03.015","article-title":"Examination of ATM, BRCA1, and BRCA2 promoter methylation in patients with pancreatic cancer","volume":"21","author":"Zhou","year":"2021","journal-title":"Pancreatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1111\/gtc.12100","article-title":"Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy","volume":"18","author":"Watanabe","year":"2013","journal-title":"Genes Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s10549-017-4552-6","article-title":"BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: A comprehensive analysis of germline mutations and somatic promoter methylation","volume":"167","author":"Brianese","year":"2018","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10549-024-07502-8","article-title":"BRCA promoter methylation in triple-negative breast cancer is preserved in xenograft models and represents a potential therapeutic marker for PARP inhibitors","volume":"209","author":"Hench","year":"2025","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1038\/s41467-020-17537-2","article-title":"Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers","volume":"11","author":"Glodzik","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Oubaddou, Y., Oukabli, M., Fenniche, S., Elktaibi, A., Elochi, M.R., Al Bouzidi, A., Qmichou, Z., Dakka, N., Diorio, C., and Richter, A. (2023). BRCA1 Promoter Hypermethylation in Malignant Breast Tumors and in the Histologically Normal Adjacent Tissues to the Tumors: Exploring Its Potential as a Biomarker and Its Clinical Significance in a Translational Approach. Genes, 14.","DOI":"10.3390\/genes14091680"},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1007\/s13277-013-1508-2","article-title":"Pyrosequencing analysis of BRCA1 methylation level in breast cancer cells","volume":"35","author":"Cai","year":"2014","journal-title":"Tumor Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s10549-011-1945-9","article-title":"Methylation of O 6-methylguanine-DNA methyltransferase (MGMT) promoter gene in triple-negative breast cancer patients","volume":"134","author":"Fumagalli","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1159\/000480196","article-title":"Association between MGMT promoter methylation and breast cancer: A meta-analysis","volume":"42","author":"An","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.clbc.2015.06.009","article-title":"Epigenetic inactivation of BRCA1 through promoter hypermethylation and its clinical importance in triple-negative breast cancer","volume":"15","author":"Yamashita","year":"2015","journal-title":"Clin. Breast Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jacot, W., Thezenas, S., Senal, R., Viglianti, C., Laberenne, A.-C., Lopez-Crapez, E., Bibeau, F., Bleuse, J.-P., Romieu, G., and Lamy, P.-J. (2013). BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-523"},{"key":"ref_40","first-page":"885","article-title":"Association of BRCA1 Promoter methylation with breast cancer in Asia: A meta-analysis","volume":"19","author":"Nindrea","year":"2018","journal-title":"Asian Pac. J. Cancer Prev. APJCP"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6485","DOI":"10.1007\/s13277-015-3339-9","article-title":"Protein expression and methylation of MGMT, a DNA repair gene and their correlation with clinicopathological parameters in invasive ductal carcinoma of the breast","volume":"36","author":"Asiaf","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27499","DOI":"10.18632\/oncotarget.8355","article-title":"Pyrosequencing quantified methylation level of BRCA1 promoter as prognostic factor for survival in breast cancer patient","volume":"7","author":"Cai","year":"2016","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10549-009-0628-2","article-title":"Gene promoter methylation is associated with increased mortality among women with breast cancer","volume":"121","author":"Xu","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1751-2980.2010.00459.x","article-title":"XRCC1 downregulated through promoter hypermethylation is involved in human gastric carcinogenesis","volume":"11","author":"Wang","year":"2010","journal-title":"J. Dig. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.juro.2010.03.044","article-title":"XPC epigenetic silence coupled with p53 alteration has a significant impact on bladder cancer outcome","volume":"184","author":"Yang","year":"2010","journal-title":"J. Urol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.1038\/sj.onc.1210284","article-title":"Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers","volume":"26","author":"Wu","year":"2007","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/s41417-025-00969-7","article-title":"Decoding BRCA1 promoter hypermethylation: A new frontier in understanding sporadic breast cancer","volume":"32","author":"Patra","year":"2025","journal-title":"Cancer Gene Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1186\/s12957-025-04001-y","article-title":"Association of progesterone receptor status with breast cancer prognosis: A meta-analysis","volume":"23","author":"Hou","year":"2025","journal-title":"World J. Surg. Oncol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T13:37:27Z","timestamp":1778679447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/14\/2\/251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["medsci14020251"],"URL":"https:\/\/doi.org\/10.3390\/medsci14020251","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]}}}