Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.
Bibliographical noteFunding Information:
We are indebted to the patients donating their tumour specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank Philipp Lorimier, Elisabeth Kirst, Emilia Müller and Juana Cuesta Valdes for their technical assistance. We furthermore thank the regional computing centre of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as the support. This work was supported by the 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.). Additional funds were provided by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., J.K.F. and E.B.); by the German federal state North Rhine Westphalia (NRW) and the European Union (European Regional Development Fund: Investing In Your Future) within PerMed NRW (grant 005-1111-0025 to R.K.T., J.W., R.B.); by the Deutsche Forschungsgemeinschaft through TH1386/3-1 (to R.K.T.) and through SFB832 (TP6 to R.K.T. and J.W.; TP5 to L.C.H.); by the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08101 to R.K.T., J.W., P.N.); by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T., R.B., J.W.); by Stand Up To Cancer– American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T.); by an NIH K12 training grant (K12 CA9060625) and by an Uniting Against Lung Cancer grant, and a Damon Runyon Clinical Investigator Award (to C.M.L.); and by AIRC and Istituto Toscano Tumori project F13/16 (to F.C.).