Abstract 1036: An integrated clinicopathologic and genomic analysis of <i>PPP2R1A</i> alterations reveals distinct patterns in uterine and ovarian cancers

Abstract Purpose: PPP2R1A (encoding the PP2A Aα subunit) mutations are increasingly associated with immune checkpoint blockade (ICB) response in gynecologic cancers. However, their distinct patterns across histologies remain unclear. We bridged this gap via a comprehensive clinicogenomic analysis of PPP2R1A-mutant tumors. Methods: We retrospectively profiled 159 Chinese patients with PPP2R1A-mutant gynecologic cancers using next-generation sequencing (NGS) in a CAP/CLIA-certified laboratory. Variant classes interrogated included single nucleotide variants (SNVs), indels, copy number alterations, and fusions. Tumors were categorized by primary site (uterine vs. ovarian) and histology. We assessed features including co-mutation patterns, pathways, tumor mutational burden (TMB), and PD-L1 expression. Results: We identified 182 PPP2R1A genomic alterations across 159 patients (SNVs/indels 95.1%; amplifications 3.8%; rearrangements 1.1%). Uterine primaries predominated (109/159, 68.6%), most commonly with endometrioid histology (48.1%). Three hotspot SNVs (R183W, P179R, and S256F) accounted for 39% of all alterations. R183W was significantly enriched in ovarian clear cell carcinoma (OCCC) compared with endometrioid carcinoma (42.1% vs 20.0%; P&amp;lt;0.05). Overall PD-L1 positivity (CPS ≥1) was 66.4% (73/110) and was strongly associated with TMB-H in uterine tumors. Notably, 11.9% of patients (19/159) carried ≥2 PPP2R1A alterations (“multi-hit”). These multi-hit cases were almost exclusively uterine endometrioid cancers, demonstrated 81.2% dual positivity (TMB-H and PD-L1+). Mean TMB was markedly higher in uterine versus ovarian tumors (118.7 vs 14.9; P&amp;lt;0.001). POLE co-mutations (25.8%) are all TMB-H, and consistently conferred hypermutation. Frequent PPP2R1A co-mutations included TP53 (61.6%), PIK3CA (57.9%), ARID1A (49.1%), and PTEN (44.7%). PTEN co-mutation was strongly enriched in uterine tumors (60.6% vs 9.8%; P&amp;lt;0.001). Conclusions: PPP2R1A alterations show distinct clinicogenomic patterns that vary by primary site and histology. Uterine PPP2R1A-mutant tumors differ clearly from ovarian tumors, with higher TMB and frequent PTEN co-mutations. In contrast, ovarian tumors, especially OCCC, tend to have low TMB and rarely show combined TMB-H/PD-L1 positivity, suggesting different underlying biological pathways. For the first time to our knowledge, we also identified a “multi-hit” PPP2R1A subgroup (11.9%), observed almost exclusively in uterine cancers that were enriched for TMB-H/PD-L1 positivity and diagnosed at early stage. These findings reinforce that PPP2R1A alterations are highly context-dependent and support the need for integrated clinicogenomic assessment when selecting patients for future immunotherapy and ICB trials. Citation Format: Kai Wang, Bo Yang, Chengyi Wang, Yannan Zhu, Jinmei Wang, Kunxu Xu, Zanmei Xu. An integrated clinicopathologic and genomic analysis of PPP2R1A alterations reveals distinct patterns in uterine and ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1036.