Abstract 1531: Cross-entity mutation analysis of lung neuroendocrine tumors sheds light into their molecular origin and identifies new therapeutic targets
Authors: Fernandez-Cuesta Lynnette , Peifer Martin , Lu Xin , Seidel Danila , Zander Thomas , Leenders Frauke , Ozretić Luka , Brustugun Odd-Terje , Field John K. , Wright Gavin , Solomon Benjamin , Buettner Reinhard , Brambilla Christian , Brambilla Elisabeth , Thomas Roman K. 
Published: May 2015

Abstract
Lung neuroendocrine tumors (LNETs) comprise small-cell lung cancer (SCLC), large-cell neuroendocrine tumors (LCNEC), and pulmonary carcinoids (PCA), and account for 25% of all lung cancer cases. The low 5-year survival rate of the highly aggressive LNETs (SCLC and LCNEC) combined with the lack of an effective treatment, suggest that understanding how these tumors arise and identifying therapeutic targets are unmet needs. We performed genome/exome, and transcriptome sequencing of 29 SCLC (Ref.1), 60 LCNEC, and 45 PCA to better understand their molecular origin and identify altered genes that may offer therapeutic opportunities.
In contrast to SCLC and LCNEC, we found that RB1 and TP53 mutations were rare events in PCA suggesting that PCA are not early progenitor lesions of SCLC or LCNEC, but arise through independent mechanisms. Moreover, GSEA analysis showed that genes of the RB1 pathway were downregulated in SCLC but not in PCA. Our data also show that inactivation of chromatin-remodeling genes, specifically genes involved in histone methylation and subunits of the SWI/SNF complex, is sufficient to drive transformation in PCA.
In a preliminary analysis of 15 LCNEC (Ref.2) we observed a predominance of mutations typical of SCLC, such as RB1, TP53, and CREBBP/EP300. In this larger series, we additionally found samples with mutations frequent in adenocarcinoma (AD) or squamous (SQ) lung cancer. We could then distinguish two well-defined groups of LCNEC: a SCLC-like group, carrying MYCL1 amplifications and mutations in both RB1 and TP53 genes; and an AD/SQ-like group, harbouring CDKN2A deletions, TTF1 amplifications, and frequent mutations in KEAP1 and STK11. Interestingly, RB1, STK11, and KEAP1 mutations happened in an almost mutually exclusive way. These data suggest that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ, and also that LNETs and non-LNETs are not completely different entities. This is already suggested by the fact that one of the resistance mechanisms of EGFR-mutant adenocarcinomas to tyrosine-kinase inhibitors is through trans-differentiation to SCLC (Ref.3).
Finally, we also identified new targetable driver genes in SCLC and LCNEC: FGFR1 amplifications were observed in 6% and 18% of the cases respectively; PTEN mutations were identified in 10% of the SCLC cases; and interestingly, one of the LCNEC samples (belonging to the SCLC-like group) harboured an activating RFWD2-NTRK1 fusion gene suggesting that fusions affecting NTRK1 may not only be a targetable opportunity for AD (Ref.4) but also for LCNEC and, based on the molecular similarities, also SCLC.
(1) Peifer and Fernandez-Cuesta et al. Nat Genetics 2012
(2) The Clinical Lung Cancer Genome Project (CLCGP) and Network Genomic Medicine (NGM) Sci Transl Med 2013
(3) Sequist et al., Sci Transl Med 2011
(4) Vaishnavi et al. Nat Medicine 2013
Citation Format: Lynnette Fernandez-Cuesta, Martin Peifer, Xin Lu, Danila Seidel, Thomas Zander, Frauke Leenders, Luka Ozretić, Odd-Terje Brustugun, John K. Field, Gavin Wright, Benjamin Solomon, Reinhard Buettner, Christian Brambilla, Elisabeth Brambilla, Roman K. Thomas. Cross-entity mutation analysis of lung neuroendocrine tumors sheds light into their molecular origin and identifies new therapeutic targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1531. doi:10.1158/1538-7445.AM2014-1531