Resident Physician UC San Diego Health San Diego, CA, United States
Background: The FOLH1 gene encodes prostate-specific membrane antigen (PSMA), which is highly expressed in endothelial cells of renal cell carcinoma (RCC). PSMA is a target for imaging and radioligands, warranting further molecular characterization. We utilized a database of molecularly profiled clear cell (cc) and non-clear cell (ncc) RCC tumors to evaluate FOLH1 expression. Histology and tumor sites were compared. We examined the relationship between angiogenic gene alterations and FOLH1 expression. Additionally, we assessed survival and time to treatment failure for cabozantinib in FOLH1- high/low groups.
Methods: Inclusion criteria were RCC patient specimens (n=1765). We utilized NextGen sequencing of DNA and RNA. FOLH1-High/Low expression were defined as ≥75th/ < 25th-percentile of RNA transcripts per million (TPM). Angiogenic, T-effector, and Myeloid expression signatures were calculated using previously defined gene sets. Kaplan-Meier estimates were calculated from time of tissue collection or therapy start.
Results: FOLH1 expression was higher in ccRCC (71.1%) compared to nccRCC (19.0 vs. 3.3 TPM, P< 0.001). FOLH1 expression varied by specimen site (45% kidney/55% metastatic, 13.6 vs. 9.9 TPM, P< 0.001). FOLH1 expression strongly correlated with angiogenic gene expression (spearman = 0.76) with similar correlation strength for endothelial cells (spearman = 0.76). No difference in survival was observed based on FOLH1 expression for ccRCC (HR 1.2, P=0.57) or nccRCC cohorts (HR 0.77, P=0.59). FOLH1-High was associated with longer cabozantinib treatment time (223 vs. 61 days, HR 0.60, P=0.08).
Conclusions: We observed differential patterns of FOLH1 by histology and tumor site. FOLH1 expression correlated with angiogenic gene expression and distinct differences in tumor microenvironment, including endothelial cell abundance. FOLH1 gene expression was positively correlated with increased duration of anti-angiogenic treatment, but not associated with mortality benefit.
