Integrative genomic proﬁling of large-cell
neuroendocrine carcinomas reveals distinct
subtypes of high-grade neuroendocrine lung
Julie George et al.
Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung
cancers, but their precise relationship has remained unclear. Here we perform a compre-
hensive 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 neu-
roendocrine proﬁle with ASCL1
, type II LCNECs bear TP53 and RB1
alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a
pattern of ASCL1
, 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
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#A full list of authors and their afﬂiations appears at the end of the paper