Stefan Ambs

Background: Racial disparities in prostate cancer (PCa) survival are inconsistently reported. Methods: We evaluated long‐term survival in 976 men from the NCI–Maryland PCa case‐control study, stratified by disease stage. Results: There were no survival differences observed between African American (AA) and European American (EA) men with Stage 1 or 2 disease. In contrast, AA men with Stage 3 or 4 PCa experienced significantly higher prostate cancer‐specific and all‐cause mortality in equal‐access Veterans Affairs (VA) and non‐VA settings. Adjustment for baseline prostate‐specific antigen (PSA) level, Gleason score, and treatment modalities attenuated but did not eliminate these differences. Conclusions: Disparate survival outcomes for AA men with PCa emerge mainly at Stage 3 or 4 diagnosis, emphasizing the importance of early detection for these men. Notably, AA patients with advanced‐stage disease were more likely to receive hormone therapy alone, a treatment pattern that may contribute to racial disparities in PCa survival.

Alterations in peripheral immunity may contribute to fatal prostate cancer and the excessive disease burden among African American (AA) men. Thus, we investigated peripheral immunity in patients with prostate cancer in association with disease outcome and AA descent. We performed single-cell RNA and T-cell receptor (TCR) sequencing using peripheral blood mononuclear cells (PBMC) from a cohort of 43 patients with prostate cancer with survival follow-up and 16 healthy controls. Analyzing 273,229 high-quality PBMCs, we observed that men who developed fatal prostate cancer (n = 20) distinctively expressed the LAG3 and TIGIT exhaustion markers in their CD8+ T effector memory cells (CD8 TEM). These men also showed a loss of type 2 conventional dendritic cells (cDC2). Further analyses revealed additional transcriptome-inferred functional differences in cDC2, CD16+ monocytes, and CD8 TEM when comparing men with and without fatal disease. Those describe cDC2 as immunosuppressed, CD16+ monocytes as proinflammatory but less cytotoxic, and CD8 TEM as chronically activated in patients with fatal disease. Comparing AA with European American patients, we observed upregulated LAG3 and TIGIT in AA PBMC. For cDC2 and CD16+ monocytes, fatal disease and AA patients showed shared marker expression. Furthermore, TCR profiling discovered an overrepresentation of large, hyperexpanded clonotypes and a lower TCR diversity among fatal disease and AA patients. Lastly, the CD8 TEM functional status and LAG3 expression in PBMC emerged as candidate predictors of disease fatality. We conclude that peripheral immunity may distinctly vary in association with disease outcome and AA descent of patients with prostate cancer.

Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet their target genes remain largely unknown. We conduct multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We develop ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation using genomic and transcriptomic data from 652 normal female tissue samples and apply these models to GWAS data of 178,534 cases and 248,300 controls for association analyses. We identify 290 genes associated with breast cancer risk, including 103 previously unreported and 46 not located at known GWAS loci, and 39 genes show distinct associations with breast cancer risk by estrogen-receptor status. Single-cell RNA sequencing and in vitro experiment data provide additional functional evidence for 169 genes. These genes are enriched in pathways implicated in breast carcinogenesis. Our study uncovers insights into breast cancer genetics and biology.

Tumor analysis of NOS2 and COX2.

Spatial dot plot of CD8+/-NOS2+/-COX2+/- phenotypes in tumor from deceased patient.

Immune and tumor quantification

Modulation of EpCAM and CD44v6+.