Age‐Associated Four‐Gene Prognostic Signature in Breast Cancer

Background Young‐onset breast cancer is associated with inferior disease‐free survival (DFS), but the contribution of additional molecular heterogeneity remains unclear. Aims To identify an exploratory age‐associated gene expression signature linked to recurrence‐related outcomes and evaluate its prognostic association. Methods and Results We analyzed clinicopathological and RNA‐sequencing data from 821 patients with Stages I–III invasive ductal or lobular carcinoma in The Cancer Genome Atlas, including 142 patients aged ≤ 45 years. Genes associated with both age and DFS were screened, followed by LASSO‐Cox and stepwise multivariable Cox regression. A four‐gene signature (Sig4: C4orf14 [NOA1], LINC01124, ZNF704, and AGFG2) was identified. Young patients had significantly worse DFS than older patients, whereas overall and disease‐specific 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‐high tumors were enriched for proliferation, cell‐cycle, DNA‐repair, metabolic, and stress‐response pathways. In METABRIC, the fixed TCGA‐derived Sig4 score was associated with worse relapse‐free survival in the overall cohort but not in patients aged ≤ 45 years. Conclusion Sig4 is an exploratory age‐associated four‐gene signature with potential general prognostic relevance in breast cancer. Its utility for risk stratification specifically in young‐onset breast cancer was not externally validated and requires confirmation in independent prospective cohorts enriched for young patients.