Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

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.

Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens?

“…The value of INSM1 in an algorithm of ≥2 neuroendocrine markers staining for biopsies to recognise LCNEC is unclear. Furthermore, recent studies have addressed the existence of different molecular subtypes of LCNEC . Proposed are the LCNEC‐SCLC with TP53/RB1 mutations recognised with IHC by loss of the RB1 protein and the LCNEC‐NSCLC subtype with STK11/KEAP/KRAS mutations and the presence of RB1 protein staining .…”

Neuroendocrine marker staining pattern categorization of small‐sized pulmonary large cell neuroendocrine carcinoma

“…Two studies have recently reported the classification of LCNEC into subgroups using next generation sequencing …”

“…George et al . classified LCNEC into two subtypes, named type I LCNEC and type II LCNEC, not only based on gene mutational profiles (such as TP53 or RB1 ) but also on neuroendocrine gene expression profiles using the RNA sequencing expression data on 69 LCNECs and 110 SCLCs . These authors found that despite their gene mutational patterns, type I LCNEC lacking of TP53 and RB1 coalteration exhibited high expression of neuroendocrine genes with closest similarity to those of SCLC, and type II LCNEC with coalteration of TP53 and RB1 revealed reduced expression of neuroendocrine genes.…”

“…Our result was consistent with that of the study by George et al . where LCNEC could be classified into two subgroups based on immunostaining patterns with the three neuroendocrine markers and sTP, which exhibited high expression of neuroendocrine markers, which were similar to sSCLC in clinicopathological features. Further studies are needed to investigate the relationship between gene mutational profiles and neuroendocrine gene expression profiles.…”

“…SCLC metastasizes lymph nodes and distant organs even in the early stage . The two types resemble each other both in clinical behavior, poor prognosis and genetic background …”