Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
Autor/innen
- J. George
- V. Walter
- M. Peifer
- L.B. Alexandrov
- D. Seidel
- F. Leenders
- L. Maas
- C. Müller
- I. Dahmen
- T.M. Delhomme
- M. Ardin
- N. Leblay
- G. Byrnes
- R. Sun
- A. De Reynies
- A. McLeer-Florin
- G. Bosco
- F. Malchers
- R. Menon
- J. Altmüller
- C. Becker
- P. Nürnberg
- V. Achter
- U. Lang
- P.M. Schneider
- M. Bogus
- M.G. Soloway
- M.D. Wilkerson
- Y. Cun
- J.D. McKay
- D. Moro-Sibilot
- C.G. Brambilla
- S. Lantuejoul
- N. Lemaitre
- A. Soltermann
- W. Weder
- V. Tischler
- O.T. Brustugun
- M. Lund-Iversen
- Å. Helland
- S. Solberg
- S. Ansén
- G. Wright
- B. Solomon
- L. Roz
- U. Pastorino
- I. Petersen
- J.H. Clement
- J. Sänger
- J. Wolf
- M. Vingron
- T. Zander
- S. Perner
- W.D. Travis
- S.A. Haas
- M. Olivier
- M. Foll
- R. Büttner
- D.N. Hayes
- E. Brambilla
- L. Fernandez-Cuesta
- R.K. Thomas
Journal
- Nature Communications
Quellenangabe
- Nat Commun 9 (1): 1048
Zusammenfassung
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 ASCL1(high)/DLL3(high)/NOTCH(low), type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1(low)/DLL3(low)/NOTCH(high), 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.