Abstract 1542: Comprehensive genome and transcriptome analyses on small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is a malignant neuroendocrine tumor of the lung accounting for 15% of all lung cancer cases. SCLC is a highly aggressive disease characterized by early metastasis and a high mortality rate of 95%. The standard of care is chemotherapy, which remains largely ineffective due to quick relapse of chemo-resistant tumors. To date, targeted therapies have not been identified for the treatment of SCLC. In order to comprehensively characterize the genomic alterations in this cancer type, we sought for a worldwide collaboration to collect rare surgical specimen of SCLC patients. Thus, we were able to study copy number alterations in 130 cases, and performed whole genome sequencing on over 78 tumor-normal pairs and transcriptome sequencing of at least 62 primary tumors and 16 SCLC cell lines. In a complementary approach we analyzed tumors derived from a murine SCLC model that was established by the conditional inactivation of Rb1 and Trp53 in lung epithelial cells (Meuwissen et al., 2003). We collected copy number alteration data for 20 mouse SCLC cases and performed exome and genome sequencing of at least 8 tumors derived from SCLC mice which additionally harbored a conditional knockout of Rbl2 (Schaffer et al., 2010). Human SCLC tumors comprise large areas of copy number alterations, revealing focal amplifications of MYC transcription factors. In line with this finding recurrent MYCL1 amplifications were also detected in murine SCLC. Human primary tumors were additionally found to harbor focal homozygous deletions of the CDKN2A locus. Furthermore, low frequent amplifications of oncogenes were identified among which therapeutic tractable FGFR1 amplifications were observed in approximately 6% of the cases. The genomic data allowed for the comprehensive characterization of the TP53 and RB1 locus at higher resolution, aiding in the identification of mutations, hemizygous and homozygous deletions, and larger genomic rearrangements. Consequently, lesions of TP53 and RB1 were found to affect both alleles in almost 100% of the cases analyzed. Other TP53 and RB1 family members were also altered in human tumor specimen thus supporting the mouse models for SCLC. In line with previous findings PTEN inactivation was found in 14% of the cases. Furthermore, recurrent mutations were detected in neuroendocrine specific genes and in chromatin and histone modifiers, among which the inactivation of the histone-acyl-transferases CREBBP and EP300 occurred at a frequency of 24%. In summary, as a continuation of our initial pilot study on 29 SCLC exomes (Peifer et al., 2012) this comprehensive large scale genomic analysis provides further insight into the complex genomic architecture of SCLC tumors and substantially improves the resolution to detect genomic alterations. This larger SCLC tumor cohort allows for the identification of low frequent alterations that might play a decisive role in the development and progression of this disease. Citation Format: Julie George, Martin Peifer, Lynnette Fernandez-Cuesta, Roman Thomas. Comprehensive genome and transcriptome analyses on small cell lung cancer. [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 1542. doi:10.1158/1538-7445.AM2014-1542