Germline Genetic Variations and Breast Cancer Prognosis: A Systematic Review and Meta-Analysis

Abstract Background Breast cancer is a complex disease with a significant global health burden. Understanding the genetic factors that influence its prognosis is crucial for improving patient outcomes. This systematic review aims to synthesize the evidence on the relationship between germline DNA variations and breast cancer prognosis. Methods A comprehensive search was conducted across PubMed, Scopus, MEDLINE, Web of Science, and QInsight to identify studies from January 2000 to June 2024 that examined associations between DNA germline variations and breast cancer prognosis, including survival and recurrence. Two reviewers independently extracted data and assessed bias. Genes were mapped and clustered using STRING, based on functional and physical protein associations. The protocol was registered on PROSPERO (CRD42022308746) and followed the PRISMA guidelines. Results 54 studies were analyzed: 37 cohort, 14 retrospective, and three case-control studies. Due to heterogeneity in study design, populations, and geography, a global meta-analysis was not feasible. Instead, we performed separate meta-analyses for Disease Free Survival (DFS) and Overall Survival (OS). The combined effect sizes for DFS were 2.72 (95% CI 1.81-3.62) and 2.53 (95% CI 1.80-3.26) for OS. Seven gene pathways, particularly those involving EGFR resistance, drug metabolism, and immune system, showed relevance to survival outcomes. Despite methodological variability, consistent evidence highlighted the prognostic value of specific germline variants. A significant lack of population diversity was observed. Conclusions This systematic review underscores the prognostic relevance of germline DNA variations in breast cancer. However, further large-scale, longitudinal studies in diverse populations must validate and integrate these associations into clinical practice.