Dissecting the Significance of Acid Phosphatase 1 Gene Alterations in Prostate Cancer.

PURPOSE

The acid phosphatase 1 () gene encodes low-molecular-weight protein tyrosine phosphatase, which is overexpressed in prostate cancer (PC) and a potential therapeutic target. We analyzed expression in primary/metastatic PC and its association with molecular profiles and clinical outcomes.

METHODS

NextGen sequencing of DNA (592-gene/whole-exome sequencing)/RNA(whole-transcriptome sequencing) was performed for 5,028 specimens. -High/-Low expression was defined as quartile (Q4/1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for -quartile-stratified samples. Gene set enrichment analysis was used for Hallmark collection of pathways. PD-L1+(≥2+, ≥5%; SP142) was tested by immunohistochemistry. Tumor microenvironment's (TME) immune cell fractions were estimated by RNA deconvolution/quanTIseq. Overall survival (OS) was assessed from initial diagnosis/treatment initiation to death/last follow-up.

RESULTS

We included 3,058 (60.8%) samples from the prostate, 634 (12.6%) from lymph node metastases (LNMs), and 1,307 (26.0%) from distant metastases (DMs). expression was higher in LNM/DM than prostate (49.8/47.9 44.1 TPM; < .0001). mutations were enriched in -Q4 (37.9%[Q4] 27.0%[Q1]; < .001) among prostate samples. Pathways associated with cell cycle regulation and oxidative phosphorylation were enriched in -Q4, whereas epithelial-mesenchymal transition and tumor necrosis factor-alpha signaling via nuclear factor kappa-light-chain-enhancer of activated B-cell pathways were enriched in -Q1. Neuroendocrine and androgen receptor signaling was increased in -Q4. M2 macrophages and natural killer cell fractions were increased, whereas T cells and M1 macrophages were decreased in -Q4. While OS differences between -Q1/Q4 were not statistically significant, there was a trend for worse OS among -Q4 prostate samples (Q4 Q1: hazard ratio [HR], 1.19 [95% CI, 0.99 to 1.42]; = .06) and DM (HR, 1.12 [95% CI, 0.93 to 1.36]; = .22) but not LNM (HR, 0.98 [95% CI, 0.74 to 1.29]; = .87).

CONCLUSION

ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting 's potential role in PC pathogenesis and novel therapeutic targeting.