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

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.

SUBMITTER: Jiang L

PROVIDER: S-EPMC4836692 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Jiang Liyan L Huang Jiaqi J Higgs Brandon W BW Hu Zhibin Z Xiao Zhan Z Yao Xin X Conley Sarah S Zhong Haihong H Liu Zheng Z Brohawn Philip P Shen Dong D Wu Song S Ge Xiaoxiao X Jiang Yue Y Zhao Yizhuo Y Lou Yuqing Y Morehouse Chris C Zhu Wei W Sebastian Yinong Y Czapiga Meggan M Oganesyan Vaheh V Fu Haihua H Niu Yanjie Y Zhang Wei W Streicher Katie K Tice David D Zhao Heng H Zhu Meng M Xu Lin L Herbst Ronald R Su Xinying X Gu Yi Y Li Shyoung S Huang Lihua L Gu Jianren J Han Baohui B Jallal Bahija B Shen Hongbing H Yao Yihong Y

PLoS genetics 20160419 4

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 ...[more]

PMID: 27093186

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Project description:BackgroundThe TP53 tumor suppressor gene plays an important role in preventing and inhibiting the growth of tumor by regulating cell cycle, apoptosis and DNA repair. Meanwhile, the TP53 gene is one of the most frequently altered gene in non-small cell lung cancer (NSCLC) patients. Mutant TP53 (TP53-MUT) may lose tumor suppressor activity and gain tumor promoting functions, which play an important role in cancer risk, therapy resistance and poor prognosis. The impact of TP53-MUT on the prognosis of NSCLC patients need to be further studied.MethodsWe obtained genomic and clinical data from The Cancer Genome Atlas (TCGA). Mutation profiles, the TMB, disease-free survival (DFS), and overall survival (OS) were compared between patients with different TP53-MUT statuses.ResultsTP53-MUTs were detected in 46.6% of patients with lung adenocarcinoma (LUAD) (264 of 566) and 82.3% of those with lung squamous cell carcinoma (LUSC) (401 of 487). The most frequently co-mutated genes in patients with LUAD carrying a TP53-MUT included classic driver genes such as epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK), while Kirsten rat sarcoma viral oncogene (KRAS) mutations and TP53-MUTs appear to be mutually exclusive. This mutual exclusivity was not observed in patients with LUSC, in whom titin (TTN) and CUB and Sushi multiple domains 3 (CSMD3) were the most frequently co-mutated genes. A higher TMB was significantly associated with TP53-MUTs in patients with LUAD but not in those with LUSC. In patients with stage I-III NSCLC who had undergone surgery, there was no significant difference in DFS between patients carrying TP53-wildtype (TP53-WT) and TP53-MUTs, irrespective of histology or mutation type. However, the presence of TP53-MUT was associated with shorter OS in patients with LUAD (49 vs. 54 months, respectively; P=0.13) and significantly longer OS in those with LUSC (62 vs. 29 months, respectively; P=0.015).ConclusionsIn contrast to most previous studies, we revealed TP53-MUT characteristic in NSCLC patients according to histology-specific differences and the association between TP53-MUT and the mutation landscape, the TMB, and the OS. These findings suggest a need for individualized management for patients with LUAD and LUSC who carry a TP53-MUT, and warrant further research.

Dataset Information

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

Publications

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

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