Ma Xiaoshi, Chen Kun, Zhang Jing, Liu Liming, Luo Jiping, Huang Kaipeng, Zhang Hongying, Liu Danni, Gou Jizhou, Feng Changyin, Zhao Xia, Li Wanying, Chen Lipeng, Yin Li, Meng Xianlin, Cheng Zhiqiang
Department of Pathology, Shenzhen Third People's Hospital (The Second Affiliated Hospital of Southern University of Science and Technology), Shenzhen, Guangdong, China.
Department of Urology, Shenzhen People's Hospital (The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, Guangdong, China.
Front Immunol. 2025 Aug 12;16:1609340. doi: 10.3389/fimmu.2025.1609340. eCollection 2025.
Pleomorphic giant cell adenocarcinoma (PGCA) of the prostate is a rare, aggressive variant characterized by multinucleated giant cells, sarcomatoid features, and resistance to conventional therapies. Despite its recognition in the WHO 2016 guidelines, the molecular drivers and clinicopathological correlates of PGCA remain poorly characterized. This study presents the first integrative clinicogenomic profiling of PGCA, revealing a novel prognostic gene signature with direct implications for diagnosis and treatment.
We conducted comprehensive clinicopathological and genomic analyses of a treatment-refractory PGCA case using histology, immunohistochemistry (IHC), whole-exome sequencing (WES), clonal evolution modeling, and multicohort validation. IHC assessed key prostate cancer markers (AR, AMACR, KLK3, PTEN, NKX3-1, VIM), while WES compared somatic alterations in PGCA, adjacent adenocarcinoma, and stromal tissue. Public datasets (prostate_dkfz_2018, prad_tcga, prad_mcspc_mskcc_2020) were used for external validation.
PGCA displayed profound pleomorphism, necrosis, and complete loss of luminal markers (AR/AMACR/KLK3), along with strong vimentin (VIM) expression, consistent with epithelial-mesenchymal transition. WES revealed PGCA-specific mutations enriched in cell-cycle and inflammatory response pathways, distinct from metabolic alterations in the adjacent adenocarcinoma. Clonal evolution analysis showed divergent progression from a shared ancestral clone. Importantly, mutations in ADAMTS7, CDH1, DRD5, MGAT5, and TP53 emerged as a robust five-gene signature predictive of biochemical recurrence, metastasis, and poor survival, validated across multiple independent cohorts.
Our study provides the first molecular roadmap of prostatic PGCA to date, establishing a novel five-gene prognostic signature and revealing fundamental insights into its pathogenesis through divergent evolution from conventional adenocarcinoma. These insights offer new opportunities for precise diagnosis, prognostic stratification, and targeted therapeutic strategies for this lethal prostate cancer variant.
前列腺多形性巨细胞腺癌（PGCA）是一种罕见的侵袭性变体，其特征为多核巨细胞、肉瘤样特征以及对传统疗法耐药。尽管在世界卫生组织2016年指南中已有所提及，但PGCA的分子驱动因素和临床病理相关性仍未得到充分描述。本研究首次对PGCA进行了综合临床基因组分析，揭示了一种对诊断和治疗具有直接意义的新型预后基因特征。
我们使用组织学、免疫组织化学（IHC）、全外显子测序（WES）、克隆进化建模和多队列验证，对一例治疗难治性PGCA病例进行了全面的临床病理和基因组分析。IHC评估了关键的前列腺癌标志物（AR、AMACR、KLK3、PTEN、NKX3-1、VIM），而WES则比较了PGCA、相邻腺癌和间质组织中的体细胞改变。公共数据集（prostate_dkfz_2018、prad_tcga、prad_mcspc_mskcc_2020）用于外部验证。
PGCA表现出严重的多形性、坏死以及管腔标志物（AR/AMACR/KLK3）的完全缺失，同时波形蛋白（VIM）表达强烈，这与上皮-间质转化一致。WES显示PGCA特异性突变富集于细胞周期和炎症反应途径，与相邻腺癌中的代谢改变不同。克隆进化分析表明，从一个共同的祖先克隆开始出现了不同的进展。重要的是，ADAMTS7、CDH1、DRD5、MGAT5和TP53中的突变成为一个强大的五基因特征，可预测生化复发、转移和不良生存，并在多个独立队列中得到验证。
我们的研究提供了迄今为止前列腺PGCA的首个分子路线图，建立了一种新型的五基因预后特征，并通过与传统腺癌的不同进化揭示了其发病机制的基本见解。这些见解为这种致命的前列腺癌变体的精确诊断、预后分层和靶向治疗策略提供了新的机会。
