PROJECT SUMMARY/ABSTRACT In the United States, prostate cancer is the most prevalent malignancy, with disproportionately higher incidence and mortality rates among black men than their white counterparts. Black-white mortality disparities have been examined with differences in treatment based on socioeconomic factors implicated. Apart from these contributors, the effect of molecular and genetic factors on racial disparity is evident. Compared to earlier studies focusing on heritable mutations and single-nucleotide polymorphisms, more recently, tissue-based genomic analyses enabled by next-generation sequencing technologies have emerged to investigate race-specific somatic alterations and their clinical implications, and have already generated promising findings. However, tissue-based genomic analysis is extremely challenging in metastatic prostate cancer because, as a bone- predominant metastatic disease, tissue samples are not always obtainable. Analyses based on circulation tumor cells (CTCs), an emerging liquid biopsy approach, can provide global snapshots of primary and metastatic tumors, and provide information on spatial and temporal heterogeneity on a scale that cannot easily be achieved through analyses of tissue biopsy samples. With recent advances in single-cell technologies, analyses of CTCs at single-cell resolution offer a noninvasive approach to characterize and monitor dynamic changes of cancers from a multidimensional perspective. Nonetheless, studies on single-cell CTC analysis have rarely been reported, partly due to the considerable technology challenges. Moreover, there is no study so far to examine the mutational landscape of CTCs in the context of racial survival disparity. Recently, we have established a comprehensive pipeline on the enrichment, enumeration, isolation, whole genome amplification, sequencing, and data analysis of single CTCs. Based on this pipeline, we were recently awarded an NCI R01 project to develop a large prospective prostate cancer patient cohort to determine mutational landscapes of single CTCs with treatment response and disease progression in metastatic prostate cancer. Intriguingly, our pilot whole- exome sequencing analysis of single CTCs showed a distinct mutational signature between black and white patients with metastatic castration-resistant prostate cancer (mCRPC). Building upon these research strengths, available resources, and preliminary data, we will conduct whole-exome sequencing of CTCs from paired black and white patients to identify race-specific mutational signatures and evaluate their associations with racial survival disparity in mCRPC. By applying the cutting-edge single-cell sequencing technology in a large ongoing multi-ethnic cohort, this proposed study has the promise to identify novel genomic biomarkers that are associated with racial survival disparity in mCRPC, which may assist in prognosis stratification, precision medicine, and optimal management of prostate cancer patie...