{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:57:03Z","timestamp":1790618223744,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Young\u2010onset breast cancer is associated with inferior disease\u2010free survival (DFS), but the contribution of additional molecular heterogeneity remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To identify an exploratory age\u2010associated gene expression signature linked to recurrence\u2010related outcomes and evaluate its prognostic association.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>We analyzed clinicopathological and RNA\u2010sequencing data from 821 patients with Stages I\u2013III invasive ductal or lobular carcinoma in The Cancer Genome Atlas, including 142 patients aged \u2264\u200945\u2009years. Genes associated with both age and DFS were screened, followed by LASSO\u2010Cox and stepwise multivariable Cox regression. A four\u2010gene signature (Sig4: C4orf14 [NOA1], LINC01124, ZNF704, and AGFG2) was identified. Young patients had significantly worse DFS than older patients, whereas overall and disease\u2010specific survival did not differ significantly. After adjustment for clinicopathological factors, young age remained associated with worse DFS. Following inclusion of the continuous Sig4 score, the age association was attenuated and no longer statistically significant, while Sig4 remained independently associated with worse DFS. Sig4\u2010high tumors were enriched for proliferation, cell\u2010cycle, DNA\u2010repair, metabolic, and stress\u2010response pathways. In METABRIC, the fixed TCGA\u2010derived Sig4 score was associated with worse relapse\u2010free survival in the overall cohort but not in patients aged \u2264\u200945\u2009years.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Sig4 is an exploratory age\u2010associated four\u2010gene signature with potential general prognostic relevance in breast cancer. Its utility for risk stratification specifically in young\u2010onset breast cancer was not externally validated and requires confirmation in independent prospective cohorts enriched for young patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70670","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:21:46Z","timestamp":1788315706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Age\u2010Associated Four\u2010Gene Prognostic Signature in Breast Cancer"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7086-896X","authenticated-orcid":false,"given":"Shiro","family":"Uchida","sequence":"first","affiliation":[{"name":"Division of Diagnostic Pathology Kikuna Memorial Hospital  Yokohama Japan"},{"name":"Department of Human Pathology Juntendo University School of Medicine  Tokyo Japan"},{"name":"Division of Pathology Shizuoka 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