Genomic and Socioeconomic Determinants of Racial Disparities in Breast Cancer Survival: Insights from the All of Us Program

<b>Background</b>: Breast cancer outcomes are worse among Black women in the U.S. compared to White women. While extensive research has focused on risk factors contributing to breast cancer; the role of genomic elements in health disparities between these racial groups remains unclear. This study aims to identify genomic variants and socioeconomic status (SES) determinants influencing racial disparities in breast cancer survival through multiple mediation analyses. <b>Methods</b>: Our investigation is based on the NIH-supported All of Us (AoU) program and analyzes 7452 female participants with malignant tumors of breast, including 5073 with genomic data. A log-rank test reveals significant racial differences in overall survival time between Black and White participants (<i>p</i>-value = 0.04). Multiple mediation analysis examines the effects of 9481 genetic variables across 23 chromosomes in explaining the racial disparity in survival, adjusting for SES variables. <b>Results</b>: 15 gene mutations, in addition to age, general health, and general quality of life, have significant effects (<i>p</i>-values < 0.001) in explaining the observed racial disparity. Mutations in TMEM132B, NARFL, SALL1, PAD12, RIPK1, ASB14, DCX, GNB1L, ARHGAP32, AL135787.1, WBP11, SLC16A12AS1, AP000345.1, IKBKB, and SUPT20H have significantly different distributions between Black and White participants. The disparity is completely explained by the included variables as the direct effect is insignificant (<i>p</i>-value = 0.73). <b>Conclusions</b>: The combined impact of SES determinants and genetic mutations can explain the observed differences in breast cancer survival among Black and White participants. Future studies will explore pathways and design in vivo and in vitro experiments to validate the functions of these genes.