Abstract：
Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and 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 prometastasis 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 NEC (LCNEC) assembled in tissue microarrays. Coexpression 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 5 distinct molecular subtypes in bladder SMC based on the 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 < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine 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 < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the 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 RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.
摘要：
现在，根据转录调节因子（NEUROD1，ASCL1，POU2F3，YAP1）和DLL3的表达对肺的小细胞癌（SMC）进行分子分类，DLL3已成为研究性治疗靶标。PLCG2已显示出具有干细胞样和前转移特征和不良预后的肺SMC的不同亚群。我们分析了这些新的神经内分泌标志物的表达及其与传统神经内分泌标志物和患者预后的关联膀胱神经内分泌癌（NEC）队列中的103个SMC和19个大细胞神经内分泌癌（LCNEC）在组织微阵列中组装。评估共表达模式，并结合详细的临床注释，包括总体（OS）和无复发生存期（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，并表现出传统神经内分泌标志物的较低表达。在33个肿瘤(32%)中记录到PLCG2表达,并且与POU2F3表达高度相关(p<0.001)。DLL3在SMC（n=72，82％）和LCNEC（n=11，85％）中均高表达。YAP1的表达富集在非神经内分泌成分中，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+肿瘤具有较短的RFS和OS(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，膀胱的NEC可以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,其特征在于传统神经内分泌标志物的较低表达。标记表达模式在SMC和LCNEC中相似。PLCG2和POU2F3的表达与较短的无复发和总生存期相关。DLL3在膀胱的SMC和LCNEC中均以高水平表达,提名它作为一个潜在的治疗靶点。
