Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

TL;DR

This study shows that PDE3A is highly expressed in gastrointestinal stromal tumors and could be a potential target for new cancer therapies.

Contribution

The study introduces a novel mouse monoclonal antibody to assess PDE3A expression in GISTs and links it to clinicopathological features.

Findings

Weak PDE3A expression correlates with lower mitotic counts and higher metastasis rates in GISTs.

PDE3A staining intensity correlates positively with CD117 expression but not with other clinicopathological variables.

PDE3A expression is consistently high in GISTs, suggesting it as a promising therapeutic target.

Abstract

Phosphodiesterase 3A (PDE3A) is an emerging therapy target in various cancers with high expression, as in the majority of gastrointestinal stromal tumors (GISTs). However, its association with clinicopathological factors and patient survival in GISTs remains unexplored. We investigated PDE3A expression using a novel mouse monoclonal antibody and immunohistochemistry in two GIST patient series consisting of 173 formalin-fixed, paraffin-embedded tissue samples on tissue microarrays. In addition, we analyzed the association between PDE3A staining intensity and clinicopathological variables and patient survival. We also assessed PDE3A mRNA expression using qPCR in a subset of the samples. We found that all GISTs expressed PDE3A. The staining pattern was weak in 6.3%, intermediate in 35.8%, and strong in 57.8% of tumors. Weak PDE3A expression was associated with a lower median mitotic count (1/50 HPF vs. 4/50 HPF vs. 5/50 HPF; p = 0.007) and higher incidence of metastases at diagnosis (28% vs. 8% vs. 3.3%; p = 0.040) than in tumors with intermediate or strong expression, respectively. PDE3A and CD117 staining intensities correlated positively (p < 0.001), but PDE3A expression showed no association with sex, age, tumor size, location, risk stratification, mutation profile, Schlafen 12 expression, or metastasis-free or overall survival. We conclude that PDE3A expression can be reliably assessed in archived tumor material using immunohistochemistry. GISTs, with their consistently high PDE3A expression, are a promising target for PDE3A-targeted therapies. This method may also aid in stratifying patients in cancers where PDE3A expression is less common.

The online version contains supplementary material available at 10.1007/s00428-025-04150-1.

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