PO.CL01.02 · 临床研究

PPP2R1A 改变的整合临床病理学和基因组分析揭示子宫和卵巢癌中的不同模式

An integrated clinicopathologic and genomic analysis of PPP2R1A alterations reveals distinct patterns in uterine and ovarian cancers

编号 1036 展板 4 时间 4/19 02:00–05:00 区域 Section 41 主讲 Kai Wang, MD;PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 2

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作者与单位 Authors & Affiliations

Kai Wang, Bo Yang, Chengyi Wang, Yannan Zhu, Jinmei Wang, Kunxu Xu, Zanmei Xu

OrigiMed, Shanghai, China

摘要 Abstract

中文摘要

目的：PPP2R1A（编码 PP2A Aalpha 亚基）突变越来越多地与妇科癌症中的免疫检查点阻断（ICB）应答相关。然而，其在不同组织学类型中的独特模式仍不明确。我们通过对 PPP2R1A 突变肿瘤的全面临床基因组分析弥合了这一空白。方法：我们在一家 CAP/CLIA 认证的实验室使用二代测序（NGS）回顾性分析了 159 例中国 PPP2R1A 突变妇科癌症患者。检测的变异类别包括单核苷酸变异（SNV）、插入缺失、拷贝数改变和融合。肿瘤按原发部位（子宫 vs 卵巢）和组织学分类。我们评估了包括共突变模式、通路、肿瘤突变负荷（TMB）和 PD-L1 表达在内的特征。结果：我们在 159 例患者中识别出 182 个 PPP2R1A 基因组改变（SNV/indel 95.1%；扩增 3.8%；重排 1.1%）。子宫原发占主导（109/159，68.6%），最常见为子宫内膜样组织学（48.1%）。三个热点 SNV（R183W、P179R 和 S256F）占所有改变的 39%。与子宫内膜样癌相比，R183W 在卵巢透明细胞癌（OCCC）中显著富集（42.1% vs 20.0%；P<0.05）。总体 PD-L1 阳性率（CPS ≥1）为 66.4%（73/110），并与子宫肿瘤中的 TMB-H 密切相关。值得注意的是，11.9% 的患者（19/159）携带 ≥2 个 PPP2R1A 改变（“多重打击”）。这些多重打击病例几乎全部为子宫内膜样癌，表现出 81.2% 的双阳性（TMB-H 和 PD-L1+）。子宫肿瘤的平均 TMB 显著高于卵巢肿瘤（118.7 vs 14.9；P<0.001）。POLE 共突变（25.8%）全部为 TMB-H，并一致地导致超突变。常见的 PPP2R1A 共突变包括 TP53（61.6%）、PIK3CA（57.9%）、ARID1A（49.1%）和 PTEN（44.7%）。PTEN 共突变在子宫肿瘤中显著富集（60.6% vs 9.8%；P<0.001）。结论：PPP2R1A 改变显示出因原发部位和组织学而异的独特临床基因组模式。子宫 PPP2R1A 突变肿瘤与卵巢肿瘤明显不同，具有更高的 TMB 和频繁的 PTEN 共突变。相反，卵巢肿瘤，尤其是 OCCC，往往具有低 TMB，很少表现出 TMB-H/PD-L1 联合阳性，提示存在不同的潜在生物学通路。据我们所知，我们首次还识别出一个“多重打击”PPP2R1A 亚组（11.9%），几乎全部见于子宫癌，富集于 TMB-H/PD-L1 阳性且在早期诊断。这些发现进一步强化了 PPP2R1A 改变高度依赖于背景的观点，并支持在为未来免疫治疗和 ICB 试验选择患者时需要进行整合的临床基因组评估。

查看英文原文 English abstract

Purpose: PPP2R1A (encoding the PP2A Aalpha 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<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<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<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.

利益披露 Disclosure

K. Wang, OrigiMed Employment, Stock Option. B. Yang, OrigiMed Employment, Stock Option. C. Wang, None. Y. Zhu, OrigiMed Employment, Stock Option. J. Wang, None. K. Xu, OrigiMed Employment. Z. Xu, OrigiMed Employment, Stock Option.

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