Differential NEUROD1, ASCL1, and POU2F3 expression defines molecular subsets of bladder small cell/neuroendocrine carcinoma with prognostic implications Journal Article
| Authors: | Akbulut, D.; Whiting, K.; Teo, M. Y.; Tallman, J. E.; Ozcan, G. G.; Basar, M.; Jia, L.; Rammal, R.; Chen, J. F.; Sarungbam, J.; Chen, Y. B.; Gopalan, A.; Fine, S. W.; Tickoo, S. K.; Mehra, R.; Baine, M.; Bochner, B. H.; Pietzak, E. J.; Bajorin, D. F.; Rosenberg, J. E.; Iyer, G.; Solit, D. B.; Reuter, V. E.; Rekhtman, N.; Ostrovnaya, I.; Al-Ahmadie, H. |
| Article Title: | Differential NEUROD1, ASCL1, and POU2F3 expression defines molecular subsets of bladder small cell/neuroendocrine carcinoma with prognostic implications |
| 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. © 2024 United States & Canadian Academy of Pathology |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; protein expression; treatment outcome; treatment response; major clinical study; overall survival; clinical feature; cancer patient; biological marker; metastasis; progression free survival; prevalence; cohort analysis; protein p53; radical cystectomy; tissue microarray; neoadjuvant chemotherapy; neuroendocrine carcinoma; small cell carcinoma; recurrence free survival; cancer prognosis; transcription factor mash1; high throughput sequencing; human; male; female; article; dll3; neurogenic differentiation factor; ascl1; transcription factor pou; neurod1; pou2f3; plcg2; phospholipase c gamma2; transcription factor 3; small cell carcinoma of the bladder |
| Journal Title: | Modern Pathology |
| Volume: | 37 |
| Issue: | 10 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2024-10-01 |
| Start Page: | 100557 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2024.100557 |
| PUBMED: | 38964503 |
| PROVIDER: | scopus |
| PMCID: | PMC11490389 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Hikmat Al-Ahmadie -- Source: Scopus |
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