Abstract 2032: Genomic landscape survey identifies SRSF1 as a key oncodriver in small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is an aggressive disease with poor survival. Large-scale sequencing studies have revealed potential disease-driving genes in various cancers, although in SCLC, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. It revealed 34,099 somatic nonsilent single nucleotide variants (SNVs) or insertion/deletions (indels), an average of 308 per patient and nonsilent/silent ratio of 1.66. Genes harboring the most recurrent SNVs or indels were TP53 (81%), CSMD3 (43%), RB1 (46%), LRP1B (38%) and OBSCN (41%). Somatic copy number variants (CNVs) were also identified including MYC (8%), KIT (17%), and SOX4 (19%), with SOX2 (67%) and multiple other genes located across a segment on chromosome 3q27.1. Genes with CN losses include RB1 (34%), RASSF1 (57%), FHIT (54%), KIF2A (16%), and CNTN3 (53%), as well as a long segment along chromosome 3p22.1. Recurrence rates of these genes affected by SNVs and CNVs were comparable to those reported previously. In addition, we found recurrent gains of Serine/Arginine Splicing Factor 1 (SRSF1) in 51% (49/96) patients as well as concordant over-expression of mRNA for those patients with gains (p = 0.005; two-tailed two-sided Welch's t-test;). Among these 96 Chinese patients, 28% had both CN gain and mRNA over-expression of SRSF1; SRSF1 CN status was evaluated by FISH assay (N = 34), the positive and negative predictive values were 57% and 69% respectively. Patients with both RNASeq and survival data were interrogated (N = 49), SRSF1 was the only gene correlating between both CN gain and mRNA over-expression as well as between over-expression and survival using a Cox proportion hazard (PH) regression model adjusting for age, gender, tumor stage, and chemotherapy status (p = 0.034; HR = 3.0). Patients with SRSF1 mRNA over-expression or CN gain demonstrated significantly worse survival. The discovery (log-rank test p = 0.062), validation (log-rank test p = 0.03), and combined patient cohort (Cox PH p = 0.021; HR = 2.1; log-rank test p = 0.005). On target in vivo studies demonstrated that SRSF1 is essential for tumorigenecity of SCLC. siRNAs (control/SRSF1)were transfected to cell lines with DNA amplification/mRNA overexpression (DMS114 and SHP-77SRSF1). Equal numbers of viable transfected cells were injected in immunocompromised mice and tumor growth was monitored for up to three weeks. SRSF1 knockdown completely suppressed the tumor growth These data strongly support SRSF1 as a therapeutic target in SCLC and provide a rationale for personalized therapy in SCLC. Citation Format: Zheng Liu, Jiaqi Huang, Brandon W. Higgs, Haihong Zhong, Dong Shen, Zhan Xiao, Xin Yao, Philip Brohawn, Xiaoxiao Ge, Zhibing Hu, Yue Jiang, Chris Morehouse, Wei Zhu, Yinong Sebastian, Meggan Czapiga, Vaheh Oganesyan, Haihua. Fu, Xinying Su, Yi Gu, Baohui Han, Ronald Herbst, Liayang Jiang, Hongbing Shen, Yihong Yao. Genomic landscape survey identifies SRSF1 as a key oncodriver in small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2032. doi:10.1158/1538-7445.AM2015-2032