Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.
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.
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Liyan
L
Jiang
Medimmune, Gaithersburg, Maryland, United States of America.
Jiaqi
J
Huang
Medimmune, Gaithersburg, Maryland, United States of America.
Brandon W
BW
Higgs
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Zhibin
Z
Hu
Medimmune, Gaithersburg, Maryland, United States of America.
Zhan
Z
Xiao
Medimmune, Gaithersburg, Maryland, United States of America.
Xin
X
Yao
Medimmune, Gaithersburg, Maryland, United States of America.
Sarah
S
Conley
Medimmune, Gaithersburg, Maryland, United States of America.
Haihong
H
Zhong
Medimmune, Gaithersburg, Maryland, United States of America.
Zheng
Z
Liu
Medimmune, Gaithersburg, Maryland, United States of America.
Philip
P
Brohawn
Medimmune, Gaithersburg, Maryland, United States of America.
Dong
D
Shen
Medimmune, Gaithersburg, Maryland, United States of America.
Song
S
Wu
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Xiaoxiao
X
Ge
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Yue
Y
Jiang
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Yizhuo
Y
Zhao
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Yuqing
Y
Lou
Medimmune, Gaithersburg, Maryland, United States of America.
Chris
C
Morehouse
Medimmune, Gaithersburg, Maryland, United States of America.
Wei
W
Zhu
Medimmune, Gaithersburg, Maryland, United States of America.
Yinong
Y
Sebastian
Medimmune, Gaithersburg, Maryland, United States of America.
Meggan
M
Czapiga
Medimmune, Gaithersburg, Maryland, United States of America.
Vaheh
V
Oganesyan
Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, China.
Haihua
H
Fu
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Yanjie
Y
Niu
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Wei
W
Zhang
Medimmune, Gaithersburg, Maryland, United States of America.
Katie
K
Streicher
Medimmune, Gaithersburg, Maryland, United States of America.
David
D
Tice
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Heng
H
Zhao
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Meng
M
Zhu
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Lin
L
Xu
Medimmune, Gaithersburg, Maryland, United States of America.
Ronald
R
Herbst
Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, China.
Xinying
X
Su
Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, China.
Yi
Y
Gu
Beijing Genomics Institute, Shenzhen GuangDong, China.
Shyoung
S
Li
Beijing Genomics Institute, Shenzhen GuangDong, China.
Lihua
L
Huang
Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jianren
J
Gu
Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Baohui
B
Han
Medimmune, Gaithersburg, Maryland, United States of America.
Bahija
B
Jallal
Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Hongbing
H
Shen
Medimmune, Gaithersburg, Maryland, United States of America.
Yihong
Y
Yao
D000328:Adult; D000368:Aged; D018288:Carcinoma, Small Cell / Q000235:genetics*; D056915:DNA Copy Number Variations; D004249:DNA Damage; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*
D015513:Oncogene Proteins; C000595779:SRSF1 protein, human; D000068103:Serine-Arginine Splicing Factors