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.
Bibliographical noteFunding Information:
This work was supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium (grant ID: 109679 to R.K.T., M.P., R.B., P.N., M.V., and S.A.H.), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.K.T., R.B., U.L., M.P. and J. W, and grant no. 01ZX1406 to M.P.), by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., E.B., and L.R.), by the Deutsche For-schungsgemeinschaft (DFG; through TH1386/3-1 to R.K.T.), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T.), by the National Institute of Health (NIH U10CA181009 to D.N.H.), by the German Cancer Consortium (DKTK) Joint Funding program, by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 16847 to L.R.), and by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396 (L.B.A.). J. G. received funding as part of the IASLC Young Investigator award. L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. We are indebted to the patients donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank the regional computing center of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as the support. We would like to acknowledge that Australian specimens were provided with assistance of the Victorian Cancer Biobank. We furthermore thank Johannes Berg, Chau Nguyen, Philipp Lorimier, Elisabeth Kirst, and César Tejerina Álvarez for their technical assistance.
© 2018 The Author(s).