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We examine the association between SLEs and BC risk using cohort and twin\u2010pair analyses with 36\u2009years of follow\u2010up in the Finnish Twin Cohort, including 10,342 women and 719\u2009BC cases. SLEs were assessed in 1981 by a questionnaire, while cancer incidence and mortality data were obtained from Finnish registries. Polygenic risk score for breast cancer (PRS\u2010BC) and DNA methylation (DNAm) profiling were used to explore the underlying genetic and epigenetic factors. Cox proportional hazards models showed a significant association between SLEs and breast cancer risk (HR\u2009=\u20091.05 per event, 95% CI: 1.02\u20131.08). As few as 2\u20133 SLEs were associated with a 24% increased risk (HR\u2009=\u20091.24, 95% CI: 1.00\u20131.54), emphasizing the impact of even a modest number of events. Within\u2010pair analyses in monozygotic twins suggested non\u2010genetic factors mediate this association. Stratification by birth cohort revealed a stronger effect in women born before 1950 (HR\u2009=\u20091.07, 95% CI: 1.01\u20131.12). While PRS\u2010BC was not significantly associated with breast cancer risk, DNAm analysis identified 42\u2009BC\u2010associated CpG sites linked to both SLE exposure and environmental BC risk. These findings were replicated in cancer\u2010free twin pairs, supporting epigenetic rather than genetic mediation. SLEs may be an independent risk factor for breast cancer, potentially mediated by epigenetic mechanisms. Further research is needed to explore the functional consequences of stress\u2010related epigenetic changes and their role in BC development across generations.<\/jats:p>","DOI":"10.1002\/ijc.70154","type":"journal-article","created":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T11:44:28Z","timestamp":1757763868000},"page":"1489-1497","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Long\u2010term impact of stressful life events on breast cancer risk: A 36\u2010year genetically informed prospective study in the Finnish Twin Cohort"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1091-7346","authenticated-orcid":false,"given":"Elissar","family":"Azzi","sequence":"first","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM) University of Helsinki  Helsinki 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