Abstract
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
Highlights
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear
Consistent with this notion, we found that type II LCNECs and some small cell lung cancer (SCLC) within this transcriptional class exhibited signs of NOTCH upregulation and low expression of neuroendocrine markers, ASCL1 and DLL3, an inhibitor of the Notch signaling pathway[37] (Fig. 3d, and Supplementary Fig. 12f)
We found no association of tumor stage with the molecular subsets found in high-grade neuroendocrine tumors (Supplementary Data 12), we observed a trend toward inferior survival in patients with SCLC, which was observed in previous studies on high-grade neuroendocrine lung tumors[18]
Summary
While genomic alterations in RB1 resulted in loss-of-nuclear Rb1 expression (P < 0.0001, Fisher’s exact test, Supplementary Fig. 3a), immunohistochemistry revealed that absence of Rb1 was confined to the LCNEC component, and evident in the combined other histological subtype (6/7 cases, Supplementary Fig. 3b, Supplementary Data 2). This may implicate shared genetic features between LCNECs and the admixtures of other histological carcinoma types. We identified—frequently deleterious—somatic alterations in functionally relevant domains of STK11 (30%) and
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