Abstract
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.
Highlights
Small cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of lung cancer worldwide with more than 180,000 cases per year [1]
SCLC patients are initially highly chemo-sensitive with response rates of greater than 80% in both limited and extensive diseases, but suffer uniform disease recurrence or progression in a very short period of time
Our study indicated that CDH10 is the most commonly and significantly mutated gene in SCLC and associated with poor survival in SCLC
Summary
Small cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of lung cancer worldwide with more than 180,000 cases per year [1]. Systematic genetics and genomics analyses of large cohorts of SCLC patients remains a challenge, primarily because SCLC usually presents as extensive disease upon diagnosis and is rarely treated surgically, causing a lack of suitable tumor specimens for comprehensive analysis. To date, these types of extensive genome-wide molecular analyses have been performed on relatively small patient cohorts, which provide utility restricted to the disease population sampled [3, 4, 5]. Clinical outcome such as survival in relation to genetic alterations remains unreported, in the SCLC Chinese patient population
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