Abstract 4590: Clinicopathological analysis of pulmonary high-grade neuroendocrine carcinoma with high expression of hepatocyte nuclear factor 4 alpha

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Abstract Pulmonary high-grade neuroendocrine carcinomas (HGNECs), including small cell carcinomas (SCLCs) and large cell neuroendocrine carcinomas (LCNECs), are highly aggressive and have a poor prognosis. The molecular subtyping of HGNECs has recently attracted attention, and Wang et al. recently proposed a cross-tissue classification framework of NECs, including the hepatocellular nuclear factor 4 alpha (HNF4A) subtype [Cancer Cell, 2024]. HNF4α, a transcription factor associated with gastrointestinal differentiation, and TTF-1 are mutually and exclusively expressed in lung adenocarcinomas; however, the characteristics of HNF4α-high HGNECs and TTF-1-high HGNECs have yet to be compared. We immunohistochemically examined the characteristics of HNF4α-high HGNECs in 83 surgically resected specimens (37 SCLCs and 46 LCNECs) and revealed that HNF4α-high and TTF-1-high HGNECs accounted for 15% (12/83) and 47% (39/83), respectively. Regarding morphology of HNF4α-high HGNECs, HNF4α-high SCLCs had a slightly more abundant cytoplasm and more obscured nuclear molding than HNF4α-low SCLCs, while HNF4α-high LCNECs were characterized by a coarse nuclear chromatin pattern and prominent nuclear atypia. The cytomorphological score referred to the previous study [Jimbo, Am J Surg Pathol. 2024] was significantly higher for HNF4α-high HGNECs than for HNF4α-low HGNECs (p<0.01). In SCLCs, HNF4α-high cases (n=3) and TTF-1-high cases (n=20) were almost confined to the neuroendocrine phenotype with high ASCL1 expression, and the expressions of HNF4α, TTF-1, and POU2F3 were mutually exclusive. Similar results were obtained for LCNECs; however, some HNF4α-high cases were positive for TTF-1 or YAP1, possibly due to the heterogeneity of LCNECs. Therefore, we investigated the heterogeneity of LCNECs and performed a spatial transcriptome analysis of one HNF4α-high LCNEC case, which revealed a mutually exclusive mixture of different subgroups characterized by HNF4A and TTF-1 expression. A whole-genome analysis of 10 LCNECs showed that NFE2L2/KEAP1 mutations were characteristic of HNF4α-positive LCNECs. A prognostic analysis revealed a significantly poorer prognosis in HNF4α-high LCNECs compared to HNF4α-low LCNECs (p<0.01). A cell line analysis showed that TTF-1-high-expressing (H446/Lu139/H889/H510A) and HNF4α-high-expressing (VMRC-LCD) lines were consistent with ASCL1-high-expressing lines. HNF4α knockdown/knock-in experiments in VMRC-LCD and SBC5 (HNF4α-negative) revealed that HNF4α promoted cell proliferation by inhibiting apoptosis. HNF4α subtype HGNECs are a unique subtype, belonging to a neuroendocrine phenotype with high ASCL1 expression and showing mutual exclusivity with the TTF-1/POU2F3 subtypes. NFE2L2/KEAP1 mutations and HNF4α itself are potential therapeutic targets for this subtype. Citation Format: Kei Asayama, Ryota Matsuoka, Aya Shiba, Daisuke Matsubara. Clinicopathological analysis of pulmonary high-grade neuroendocrine carcinoma with high expression of hepatocyte nuclear factor 4 alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4590.

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