Clinicopathologic, Cellular, and Molecular Analyses of Pulmonary Neuroendocrine Carcinoma With High Expression of Hepatocyte Nuclear Factor 4 Alpha

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Pulmonary neuroendocrine carcinoma (NEC), including small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), is highly aggressive and has a poor prognosis. The molecular subtyping of NECs has recently attracted attention, and we identified a new NEC subtype, the hepatocyte nuclear factor 4α (HNF4α) subtype. 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 NEC and TTF-1-high NEC have yet to be compared. We immunohistochemically examined the characteristics of HNF4α-high NEC in 83 surgically resected specimens (37 SCLCs and 46 LCNECs) and revealed that HNF4α-high and TTF-1-high NEC accounted for 15% (12/83) and 47% (39/83), respectively. 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 LCNEC. Therefore, we investigated the heterogeneity of LCNEC and performed a spatial transcriptome analysis of 1 HNF4α-high LCNEC case, which revealed a mutually exclusive mixture of different subgroups characterized by HNF4A and NKX2-1 (TTF-1) expressions. A whole-genome analysis of 10 LCNECs showed that NFE2L2/KEAP1 mutations were characteristic of HNF4α-positive LCNECs. A prognostic analysis revealed a significantly worse prognosis in HNF4α-high LCNECs than in HNF4α-low LCNECs. A cell line analysis showed that TTF-1-high-expressing (Lu139/H889/H510A) and HNF4α-high-expressing (VMRC-LCD/H810) 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. The HNF4α-subtype of pulmonary NEC is a unique subtype, characterized by a neuroendocrine phenotype with high ASCL1 expression and mutual exclusivity with the TTF-1/POU2F3 subtypes. NFE2L2/KEAP1 mutations and HNF4α itself are potential therapeutic targets for this subtype.

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