Multilayer Analysis of Ethnically Diverse Blood and Urine Biomarkers for Breast Cancer Risk and Prognosis

Breast cancer (BC) is one of the most common malignancies among women globally, characterized by complex pathogenesis involving various biomarkers present in blood and urine. To enhance understanding of the genetic associations between biomarkers and BC via multidimensional, cross ethnic investigations. Based on GWAS data of 35 blood and urine biomarkers from European populations, we adopted multiple analysis strategies including univariable Mendelian randomization (MR) analysis, reverse MR analysis, sensitivity analysis and multivariate MR to identify potential biomarkers associated with BC risk and survival. Our initial analysis included 122,977 BC and 105,974 controls of European ancestry. Building upon these findings, we conducted cross ethnic validation by applying the same analyses to East Asian populations using data from the IEU GWAS database, which included 5,552 BC and 89,731 controls. This step allowed us to investigate the universality and heterogeneity of our identified biomarkers across different ancestries. Subsequently, utilizing clinical laboratory detection data from multiple regions in China, we performed differential analyses and survival assessments on these potential biomarkers to evaluate their clinical relevance and utility. Notably, we leveraged Luzhou's clinical data to integrate HDL-C with conventional tumor markers (CEA, CA125, CA153) into a machine learning model, comparing its diagnostic efficacy against tumor marker combination. Our study validated associations of ALP, HDL-C, TG, SHBG, and IGF-1 with BC risk, reinforcing the reliability of these findings. Moreover, notable interethnic disparities emerged in the association between HDL-C and BC risk, where in HDL-C demonstrates a contrasting role: acting as a genetic protective agent against BC and suggesting promise as an auxiliary diagnostic marker in East Asian populations, yet inversely, it serves as a genetic dangerous predictor in European populations. Analyzing BC subtypes, we identified associations of HDL-C, TG, SHBG, and CRP with ERBC, while ERBC showed associations with GLU, urinary creatinine and microalbuminuria, underscoring subtype-specific genetic characteristics critical for personalized prevention and treatment strategies. Overall, this comprehensive study, by traversing the intricate landscape of genetic associations across ethnic boundaries and employing advanced analytical methodologies, not only uncovers the complex interplay between key biomarkers and BC susceptibility but also highlights the significance of ethnic-specific differences in the role of HDL-C. By enhancing the diagnostic power of a tailored biomarker panel through machine learning, this study contributes to the advancement of precision medicine in BC, offering strategies tailored to the unique genetic profiles and biomarker patterns across diverse populations.