Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type–specific RNA splicing was discovered and analyzed across tissues within an individual.

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.

The use of race in medicine has recently come to a reckoning, 1,2 and the field of cancer genomics is not exempt from this critical introspection. Race must be understood as a social construct in scientific pursuits, yet equitable genomics research requires adequate racial representation and diversity. 3 To overcome this challenge, large registries of real-world genetic data have been assembled to accelerate progress and discovery. These registries have been used previously to describe novel associations of genetic mutations with race in various tumors. 4,5 However, caution must be exercised when interpreting discoveries on the basis of retrospective tumor molecular genotyping given the multiple caveats surrounding sample acquisition and the definition of race itself in these registries. Significant differences found between races may represent confounded associations that are ultimately spurious. In addition, most registries largely over-represent White patients. 6 Thus, we sought to update the aforementioned analyses 4,5 with a larger set of tumor types by race to assess validity and robustness of previous findings and enable further biomarker discovery. Using data extracted from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE), version 8.1, 7 we analyzed tumor mutational profiles from the top five leading causes of new cancer cases or deaths in the United States for 2021 (breast, colorectal, lung, pancreas, and prostate) 8 across three reported races (Asian, White, and Black) to detect differences in mutational frequencies or distributions between racial groups. Analysis was limited to tumors sequenced by Memorial Sloan Kettering (MSK) and Dana-Farber Cancer Institute (DFCI), as most evaluated tumor types in the GENIEv8.1 registry (66%) are captured by MSK/DFCI sequencing initiatives (Data Supplement).