Abstract
Abstract IMPORTANCE African American (AA) breast cancer patients have worse outcomes than Caucasian Americans (CAs). DNA damage repair (DDR) genes drive poor outcome in CA estrogen receptor (ER)+ breast cancer patients. Whether DDR genes similarly impact survival in AAs is unknown. Identifying AA-specific patterns of DDR dysregulation could change how we tailor predictive/prognostic biomarkers. OBJECTIVE To characterize DDR dysregulation in ER+ AA patient tumors and test associations with clinical outcome. DESIGN SETTINGS AND PARTICIPANTS Three independent tumor, and two normal breast datasets were analyzed. Tumor datasets: (1) GSE78958 (2) GSE18229 (3) The Cancer Genome Atlas (TCGA). Normal datasets: (4) GSE43973 (5) GSE50939. MAIN OUTCOME AND MEASURES Up/down-regulation of 104 DDR genes was assessed in AA samples vs CAs. Survival associations were assessed for genes dysregulated in multiple datasets. RESULTS Overall, RNA levels of single strand break repair (SSBR) genes were downregulated in AA tumors and double strand break repair (DSBR) genes were upregulated compared to CAs. While SSBR downregulation was mainly detected in tumors, DSBR upregulation was detectable in both tumor and normal breast AA samples. Seven specific DDR genes identified as dysregulated in AAs vs CAs in multiple datasets associated with poor survival. A subset of tumors with simultaneous dysregulation of homologous recombination and single strand break repair genes was enriched in AAs and had associated consistently with poor survival. CONCLUSION AND RELEVANCE Overall, these results constitute the first systematic analysis of differences in DDR regulation in AA ER+ tumors and normal tissue vs CAs. We identify a profile of DDR dysregulation enriched in AA patients, which associates with poor outcome. These results suggest a distinct molecular mechanism of DDR regulation in AAs that lays the groundwork for refining biomarker profiles by race and improving precision medicine for underserved populations. Competing Interest Statement The authors have declared no competing interest. Footnotes * Key Points * Question: Do ER+/HER2− breast tumors in African American women have a distinct pattern of DNA damage repair dysregulation that contribute to poor outcome? * Findings: In this cohort study a distinct DNA damage repair dysregulation was detected in African American women with ER+/HER2− breast cancer. Molecular differences in RNA levels and mutational frequency were observed between African American and Caucasian tumors. Most strikingly, simultaneous downregulation of two DNA repair pathways was enriched in African American patients and associated with poor survival. * Meaning: Disparity in breast cancer outcome between African American and Caucasian women is well established. Our study, for the first time, creates a map of the DNA repair landscape in ER+/HER2− breast cancer from African American women and associates it significantly with worse survival outcome.