Cross‐Cohort Characterization of an LHB‐Associated Transcriptomic State in Prostate Cancer

ABSTRACT Background We sought to characterize an LHB‐associated tumor transcriptomic state across public prostate cancer datasets. Tumor LHB expression and the correlation‐derived signature were treated as molecular measurements only; serum luteinizing hormone and testosterone were not available or analyzed. Methods In 501 TCGA‐PRAD tumors, the 25 genes most positively and 25 most negatively correlated with LHB defined a direction‐weighted signature. The frozen score was projected without refitting into GSE54460, GSE116918, and two GSE21034 platform views. Cohort‐specific grade, biochemical recurrence, and compact expression programs were evaluated. Program genes did not overlap the signature, and LHB was excluded from steroidogenesis. In GSE176031, upper and lower signature‐score quartiles were compared within each of 53 samples. Results The score was higher in high‐grade TCGA‐PRAD tumors (mean difference, 0.327; P = 7.12 × 10 −9 ) and had positive but heterogeneous grade differences in the external datasets. Across all five bulk views, the score correlated negatively with androgen receptor signaling ( r = −0.365 to −0.627) and positively with cell cycle ( r = 0.283–0.692) and epithelial‐mesenchymal transition ( r = 0.217–0.734). Direct LHB transcripts were detected in 30 of 53,765 cells. Sample‐level single‐cell contrasts showed lower androgen receptor signaling and higher cell‐cycle and epithelial‐mesenchymal‐transition scores in signature‐high epithelial states; the LHB‐excluded steroidogenesis contrast was near zero. Conclusions The LHB‐correlation‐derived signature identifies an AR‐low, proliferative, mesenchymal‐associated expression state across datasets. It does not measure circulating hormones, establish LHB‐dependent biology, or support clinical use. Paired molecular and functional studies are required.