Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.
Julie GeorgeVonn WalterMartin PeiferLudmil B AlexandrovDanila SeidelFrauke LeendersLukas MaasChristian MüllerIlona DahmenTiffany M DelhommeMaude ArdinNoemie LeblayGraham ByrnesRuping SunAurélien De ReyniesAnne McLeer-FlorinGraziella BoscoFlorian MalchersRoopika MenonJanine AltmüllerChristian BeckerPeter NürnbergViktor AchterUlrich LangPeter M SchneiderMagdalena BogusMatthew G SolowayMatthew D WilkersonYupeng CunJames D McKayDenis Moro-SibilotChristian G BrambillaSylvie LantuejoulNicolas LemaitreAlex SoltermannWalter WederVerena TischlerOdd Terje BrustugunMarius Lund-IversenÅslaug HellandSteinar SolbergSascha AnsénGavin WrightBenjamin SolomonLuca RozUgo PastorinoIver PetersenJoachim H ClementJörg SängerJürgen WolfMartin VingronThomas ZanderSven PernerWilliam D TravisStefan A HaasMagali OlivierMatthieu FollReinhard BüttnerDavid Neil HayesElisabeth BrambillaLynnette Fernandez-CuestaRoman K ThomasPublished in: Nature communications (2018)
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.
Keyphrases
- high grade
- single cell
- low grade
- squamous cell
- copy number
- transcription factor
- gene expression
- cell therapy
- stem cells
- healthcare
- rna seq
- cell proliferation
- signaling pathway
- pulmonary hypertension
- social media
- bone marrow
- dna methylation
- mesenchymal stem cells
- drug delivery
- heat stress
- oxidative stress
- health information
- single molecule