Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer

Liyan Jiang, Jiaqi Huang, Brandon W. Higgs, Zhibin Hu, Zhan Xiao, Xin Yao, Sarah Conley, Haihong Zhong, Zheng Liu, Philip Brohawn, Dong Shen, Song Wu, Xiaoxiao Ge, Yue Jiang, Yizhuo Zhao, Yuqing Lou, Chris Morehouse, Wei Zhu, Yinong Sebastian, Meggan Czapiga, Vaheh Oganesyan, Haihua Fu, Yanjie Niu, Wei Zhang, Katie Streicher, David Tice, Heng Zhao, Meng Zhu, Lin Xu, Ronald Herbst, Xinying Su, Yi Gu, Shyoung Li, Lihua Huang, Jianren Gu, Baohui Han, Bahija Jallal, Hongbing Shen, Yihong Yao

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, 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. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.