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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>De-escalation of axillary surgery has resulted in the loss of pathologic nodal information, yet the extent of lymph node involvement remains an important determinant of treatment decisions in estrogen receptor-positive (ER+)\/HER2\u2212 disease. We examined whether primary tumors differed molecularly according to the extent of this regional dissemination. Genome-wide DNA methylation profiling of primary ER+\/HER2\u2212 tumors from 47 patients with pN1 (n = 29) vs. &gt;pN1 (n = 18) disease showed differences concentrated at promoters of developmental and cell-adhesion genes. By integrating methylomes with transcriptomes from the TCGA-BRCA cohort (n = 148) and clinical outcomes from KM Plotter (RFS, n = 1154; OS, n = 442; DMFS, n = 423), we identified four genes (ARL10, RIC3, CXCL14, KCNH2) showing concordant molecular and clinical associations, from which we derived the Lymph-node Involvement Outcome Numerator (LION) score. Lower LION scores were observed in metastatic lesions from the AURORA US cohort (n = 45). In SCAN-B (n = 3969), lower scores were associated with shorter distant recurrence-free intervals (HR = 0.38; 95% CI 0.23\u20130.62); this association persisted after adjustment for age, nodal and tumor category but was lost after adjustment for histological grade (HR = 0.83; 95% CI 0.48\u20131.44), indicating that the score and grade capture overlapping biology. These findings suggest that primary tumors already display coordinated epigenetic and transcriptional alterations associated with the extent of metastatic dissemination.<\/jats:p>","DOI":"10.3390\/ijms27177901","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:50:44Z","timestamp":1788529844000},"page":"7901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Primary Tumor Epigenetic and Transcriptomic Alterations Associated with Nodal Burden and Metastatic Risk in ER+\/HER2\u2212 Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Sandra","family":"I\u00f1iguez-Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"},{"name":"Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, 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E.","family":"Factor","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University, Durham, NC 27710, USA"},{"name":"Duke Cancer Institute, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3258-8852","authenticated-orcid":false,"given":"Diego M.","family":"Marzese","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA"},{"name":"Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain"},{"name":"Duke Cancer Institute, Durham, NC 27710, 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