Dissecting the significance of ACP1 gene alterations in prostate cancer (PCa).
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Dissecting the significance of ACP1 gene alterations in prostate cancer (PCa).

Abstract

5025 Background: The acid phosphatase 1 ( ACP1) gene encodes low molecular weight protein tyrosine phosphatase (LMPTP), which is overexpressed in PCa. Previous studies demonstrate that LMPTP plays a critical role in PCa growth and metastasis and is evolving as a potential therapeutic target. Thus, we analyzed ACP1 expression in primary and metastatic PCa samples and the association of ACP1 with molecular profiles and clinical outcomes. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed for PCa specimens (n=5028) submitted to Caris Life Sciences. ACP1-High/Low expression was defined as quartile 4 (Q4) and 1 (Q1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for samples stratified by ACP1 expression quartiles. Gene set enrichment analysis was used to assess the Hallmark collection of cancer pathways. Tumor cell PD-L1+ status (≥2+, ≥5%; SP142) was tested by immunohistochemistry. Immune cell fractions in the tumor microenvironment (TME) were estimated by RNA deconvolution using QuanTIseq. Overall survival (OS) was assessed from the time of specimen collection to death or last follow-up, with hazard ratio (HR) calculated using the Cox proportional hazards model, and P values calculated using the log-rank test. Results: Samples included 3058 (60.8%) derived from the prostate, 634 (12.6%) from lymph node metastases (LNM), and 1307 (26.0%) from distant metastases (DM). ACP1 expression was higher in LNM and DM than in the prostate (49.8 and 47.9, respectively, vs 44.1 TPM, p<0.0001 each). TP53 mutations were enriched in the highest ACP1 quartile (37.9% Q4 vs 27.0% Q1, p<0.001) among prostate samples but not LNM or DM. Pathways associated with cell cycle regulation, oxidative phosphorylation, and androgen response were enriched in Q4, while epithelial-mesenchymal transition and TNF-α signaling via NFKB pathways were enriched in Q1. Both neuroendocrine and androgen receptor signaling increased in Q4. M2 macrophages and NK cell fractions were increased, while T cells and M1 macrophages were decreased in Q4. PD-L1 expression did not differ by ACP1 expression. High ACP1 was associated with worse OS among prostate tumors (63.4 vs 86.3 months (mos) in ACP1-high vs low tumors, HR 1.5, 95% CI 1.3-1.7, p<0.0001) and DM (22.0 vs 27.7 mos in ACP1-high vs low tumors, HR 1.2, 95% CI 1.0-1.4, p<0.05) but not LNM (31.9 vs 30.9 mos in ACP1-high vs low tumors, HR 1.0, 95% CI 0.8-1.3, p=0.88). OS from the start of ARSI and taxane chemotherapy was similar in ACP1 high/low groups across prostate, LNM, and DM. Conclusions: In the largest study investigating the significance of ACP1 expression in PCa, we demonstrate that ACP1-high tumors exhibit a distinct molecular profile enriched for TP53 alterations and associated with a ‘cold’ TME. Our findings may provide a rationale for novel therapeutic targeting of ACP1-high tumors.

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