肺癌小细胞癌 (SMC) 现在根据转录调节因子（NEUROD1、ASCL1、POU2F3、YAP1）和 DLL3 的表达进行分子分类，DLL3 已成为研究治疗靶点。 PLCG2 已被证明可以识别具有干细胞样和促转移特征以及不良预后的肺 SMC 的独特亚群。我们在由 103 个 SMC 和 19 个大细胞神经内分泌癌 (LCNEC) 组成的膀胱神经内分泌癌 (NEC) 队列中分析了这些新型神经内分泌标记物的表达及其与传统神经内分泌标记物和患者结果的关系，这些膀胱神经内分泌癌 (NEC) 由组装在组织微阵列中的 103 个 SMC 和 19 个大细胞神经内分泌癌 (LCNEC) 组成。评估共表达模式并与详细的临床注释相结合，包括总体（OS）和无复发生存（RFS）以及对新辅助/辅助化疗的反应。我们根据 ASCL1、NEUROD1 和 POU2F3 的表达确定了膀胱 SMC 中五种不同的分子亚型：ASCL1 /NEUROD1- (n=33; 34%)、ASCL1-/NEUROD1 (n=21; 21%)、ASCL1 /NEUROD1 (n =17; 17%)、POU2F3 (n=22, 22%) 和 ASCL1-/NEUROD1-/POU2F3- (n=5, 5%)。 POU2F3 肿瘤与表达 ASCL1 和 NEUROD1 的肿瘤相互排斥，并且传统神经内分泌标志物的表达较低。 PLCG2 表达在 33 个肿瘤 (32%) 中被发现，并且与 POU2F3 表达高度相关 (p < 0.001)。 DLL3 在 SMC (n=72, 82%) 和 LCNEC (n=11, 85%) 中表达较高。 YAP1 表达在非神经内分泌成分中富集，并与所有神经内分泌标志物呈负相关。在接受根治性膀胱切除术的无转移性疾病的患者中，PLCG2或POU2F3肿瘤的RFS和OS较短（p<0.05），但它们的表达与转移状态或对新辅助/辅助化疗的反应无关。总之，根据 ASCL1、NEUROD1 和 POU2F3 的表达，膀胱 NEC 可分为不同的分子亚型。表达 POU2F3 的肿瘤代表膀胱 NEC 的 ASCL1/NEUROD1 阴性子集，其特征是传统神经内分泌标志物表达较低。 SMC 和 LCNEC 中的标志物表达模式相似。 PLCG2 和 POU2F3 的表达与较短的无复发生存期和总生存期相关。 DLL3 在膀胱 SMC 和 LCNEC 中高水平表达，将其提名为潜在的治疗靶点。版权所有 © 2024。由 Elsevier Inc. 出版。

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and pro-metastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell neuroendocrine carcinomas (LCNEC) assembled in tissue microarrays. Co-expression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified five distinct molecular subtypes in bladder SMC based on expression of ASCL1, NEUROD1 and POU2F3: ASCL1+/NEUROD1- (n=33; 34%), ASCL1-/NEUROD1+ (n=21; 21%), ASCL1+/NEUROD1+ (n=17; 17%), POU2F3+ (n=22, 22%), and ASCL1-/NEUROD1-/POU2F3- (n=5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (p < 0.001). DLL3 expression was high in both SMC (n=72, 82%) and LCNEC (n=11, 85%). YAP1 expression was enriched in non- neuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (p<0.05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1 and POU2F3. POU2F3 expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter recurrence-free and overall survival. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.Copyright © 2024. Published by Elsevier Inc.