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Pulmonary grade-1 typical (TC) and grade-2 atypical (AC) carcinoids share molecular characteristics with grade-3 large-cell neuroendocrine carcinoma (LCNEC) despite the distinct clinical behaviors. Most carcinoids can be surgically resected, however, limited treatment options exist for metastatic disease, present in 10-23% of TC and 40-50% of AC. Comprehensive genomic studies could help identify better therapeutic opportunities, novel diagnostic markers, and provide insight on the mechanisms responsible for the increased aggressiveness of AC versus TC. Such studies are rare due to the limited availability of suitable material. We have established a multi-center collaboration that has given us access to a unique collection of samples. We have already characterized 40 TC and 60 LCNEC genomes/exomes, and 61 TC, 8 AC and 69 LCNEC trancriptomes (published data). In the present study, we have performed whole-exome and transcriptome sequencing on 20 AC patients. Methylation data from 850K Illumina arrays were also generated for these samples, and for a subset of 20 TC and 20 LCNEC previously mentioned. When comparing the mutational data on AC with that of TC and LCNEC, we have found that similar to TC, AC harbor recurrent alterations in chromatin remodeling genes (such as MEN1 and ARID1A). They also carry alterations in genes involved in other cancer-related pathways (based on STRING), such as cell motility and cell death explaining their more aggressive phenotype. Integrative clustering analysis (MOFA and iCLUSTER) based on expression and methylation data tends to classify carcinoids into four groups: groups 1 and 2 are mostly composed of females with TC, and differ by their age composition and smoking status (Fisher's exact test p=0.008 and 0.03, respectively). Groups 3 and 4 are mostly composed of males with AC (Fisher's exact test for tumor type p=8x10-5). When including the LCNEC data, the samples from group 3 cluster with LCNEC, suggesting that AC can display a variety of expression and methylation patterns that may be linked to aggressiveness. This result was supported by the better survival of groups 1 and 2 compared to groups 3 and 4 (log-rank p=0.02), for which survival was similar to that of patients with LCNEC. Here, we present for the first time: (i) a multi-omics study on AC; (ii) the methylome characterization of TC, AC, and LCNEC; and (iii) the results of a comparative analysis of TC, AC, and LCNEC based on their molecular characteristics. We have identified the genes and pathways that might explain the progression from low-grade TC to intermediate-grade AC. Our expression and methylation data also supports the existence of a “super-AC” group, which clusters with LCNEC. Finally, we have identified a panel of molecular alterations that may help pathologist distinguishing between these three entities. NL and NA contributed equally. LFC and MF jointly supervised this work. Citation Format: Noémie Leblay, Nicolas Alcala, David Hervás Marin, Tiffany M. Delhomme, Théo Giffon, Akram Ghantous, Amélie Chabrier, Cyrille Cuenin, Janine Altmueller, Geoffroy Durand, Catherine Voegele, Philippe Lorimier, Anne-Claire Toffart, Jules Derks, Odd Terje Brustugun, Joachim H. Clement, Joerg Saenger, John K. Field, Alex Soltermann, Gavin M. Wright, Luca Roz, Lucia Anna Muscarella, Paolo Graziano, Zdenko Herceg, Ernst-Jan Speel, Peter Nuernberg, James McKay, Nicolas Girard, Sylvie Lantuejoul, Juan Sandoval, Elisabeth Brambilla, Matthieu Foll, Lynnette Fernandez-Cuesta. Multi-omics comparative analyses of pulmonary typical carcinoids, atypical carcinoids, and large-cell neuroendocrine carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5358.