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Summary: Background: Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known. Methods: Participants were 3110 men of African and European ancestries ages 45–70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45–59 years, and 60–70 years old). Association estimates are per standard deviation change in the PGS. Findings: The median age was 56.6 years, and 2118 (68%) participants were 45–59 years. The median (IQR) baseline PSA level was 1.0 (0.6–1.7) ng/mL. Among men ages 45–59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17–1.57], p = 4.5 × 10−5), an ICD code for elevated PSA (HR = 1.30 [1.12–1.52], p = 8.0 × 10−4), a urological evaluation (HR = 1.34 [1.14–1.57], p = 4.8 × 10−4), and undergoing a prostate biopsy (HR = 1.35 [1.11–1.64], p = 0.002). Among men ages 60–70, association effect sizes were smaller and not significant. Interpretation: A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45–59 years. Funding: National Institutes of Health (NIH).

The molecular and cellular underpinnings of cribriform prostate cancer aggressiveness remain to be explored. Here, the authors perform single-cell RNA-sequencing, TCR sequencing and histology and reveal cancer cell intrinsic pathways and an immunosuppressive tumour microenvironment.

Abstract Outcomes for men with localized prostate cancer vary widely, with some men effectively managed without treatment on active surveillance, while other men rapidly progress to metastatic disease despite curative‐intent therapies. One of the strongest prognostic indicators of outcome is grade groups based on the Gleason grading system. Gleason grade 4 prostate cancer with cribriform morphology is associated with adverse outcomes and can be utilized clinically to improve risk stratification. The underpinnings of disease aggressiveness associated with cribriform architecture are not fully understood. Most studies have focused on genetic and molecular alterations in cribriform tumor cells; however, less is known about the tumor microenvironment in cribriform prostate cancer. Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts in the tumor microenvironment that impact cancer aggressiveness. The overall goal of this study was to determine if cribriform prostate cancers are associated with a unique repertoire of CAFs. Radical prostatectomy whole‐tissue sections were analyzed for the expression of fibroblast markers (ASPN in combination with FAP, THY1, ENG, NT5E, TNC, and PDGFRβ) in stroma adjacent to benign glands and in Gleason grade 3, Gleason grade 4 cribriform, and Gleason grade 4 noncribriform prostate cancer by RNAscope®. Halo® Software was used to quantify percent positive stromal cells and expression per positive cell. The fibroblast subtypes enriched in prostate cancer were highly heterogeneous. Both overlapping and distinct populations of low abundant fibroblast subtypes in benign prostate stroma were enriched in Gleason grade 4 prostate cancer with cribriform morphology compared to Gleason grade 4 prostate cancer with noncribriform morphology and Gleason grade 3 prostate cancer. In addition, gene expression was distinctly altered in CAF subtypes adjacent to cribriform prostate cancer. Overall, these studies suggest that cribriform prostate cancer has a unique tumor microenvironment that may distinguish it from other Gleason grade 4 morphologies and lower Gleason grades.