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

Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, Conley S, Zhong H, Liu Z, Brohawn P, Shen D, Wu S, Ge X, Jiang Y, Zhao Y, Lou Y, Morehouse C, Zhu W, Sebastian Y, Czapiga M, Oganesyan V, Fu H, Niu Y, Zhang W, Streicher K, Tice D, Zhao H, Zhu M, Xu L, Herbst R, Su X, Gu Y, Li S, Huang L, Gu J, Han B, Jallal B, Shen H, Yao Y - PLoS Genet. (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

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.

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SRSF1 CN gain and mRNA expression correlates with survival.A: The time-to-event analysis schema with available patient specimens. In the time-to-event analyses, 96 Chinese primary SCLC patients with clinical outcome were divided into training and test cohorts according to the availabilities of matched normal, RNAseq and survival outcome information. The training set includes 22 patients with each patient having tumor and normal WES data and survival outcome. The test set includes 74 patient tumors only. Each patient has WES data from tumor and survival outcome. Among those patients, 48 patients have WES, RNAseq data, and survival outcome. b) SRSF1 mRNA expression in CN gain group and no CN gain group (p = Welch’s t-test). c) Kaplan-Meier (KM) curves comparing survival between SRSF1 low and high mRNA expression groups (n = 48). Similarly, KM curves used to evaluate the difference of survival between different SRSF1 CN statuses in d) discovery set (n = 22), e) validation set (n = 74), and f) combination of discovery set and validation set (n = 96). p* = log-rank test; p = Cox PH regression model; HR = hazard ratio.
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pgen.1005895.g003: SRSF1 CN gain and mRNA expression correlates with survival.A: The time-to-event analysis schema with available patient specimens. In the time-to-event analyses, 96 Chinese primary SCLC patients with clinical outcome were divided into training and test cohorts according to the availabilities of matched normal, RNAseq and survival outcome information. The training set includes 22 patients with each patient having tumor and normal WES data and survival outcome. The test set includes 74 patient tumors only. Each patient has WES data from tumor and survival outcome. Among those patients, 48 patients have WES, RNAseq data, and survival outcome. b) SRSF1 mRNA expression in CN gain group and no CN gain group (p = Welch’s t-test). c) Kaplan-Meier (KM) curves comparing survival between SRSF1 low and high mRNA expression groups (n = 48). Similarly, KM curves used to evaluate the difference of survival between different SRSF1 CN statuses in d) discovery set (n = 22), e) validation set (n = 74), and f) combination of discovery set and validation set (n = 96). p* = log-rank test; p = Cox PH regression model; HR = hazard ratio.

Mentions: Somatic copy number variants (CNVs) were identified from exome-sequencing data. Our results confirmed key oncogenic genes with recurrent CN gains/amplifications that were previously reported in SCLC [3, 5, 15,16,17], including MYC (8%), KIT (16%), and SOX2 (67%). Significant copy number gains or amplifications were observed across a cluster on chromosome 3q26-29 [5] (S5 Table). Genes with CN losses previously reported in SCLC [2, 4, 5] include RB1 (34%), RASSF1 (57%), FHIT (54%), KIF2A (16%), and PTEN (13%). A long segment along chromosome 3p22 was also detected to have significant CN loss. Recurrence rates of these genes affected by CNVs were comparable to those reported previously [3, 5]. In addition, we found recurrent gains of SRSF1 (50%) as well as concordant over-expression of mRNA for those patients with gains (p = 0.005; two-tailed two-sided Welch’s t-test; Fig 3A). Among these 96 Chinese patients, 28% had both CN gain and mRNA over-expression of SRSF1; in an independent cohort of 25 Caucasian SCLC patients (commercially purchased specimens–see Methods), we identified 32% with the same result. Further, SRSF1 CN gain was determined to be 30% (8/27 SCLC patients) in a re-analysis of the available WES data published from a previous Caucasian SCLC patient cohort–a result very similar between both Caucasian SCLC cohorts [3]. CN gains/amplifications or losses and somatic SNVs for relevant genes are summarized in S1 Fig.


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

Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, Conley S, Zhong H, Liu Z, Brohawn P, Shen D, Wu S, Ge X, Jiang Y, Zhao Y, Lou Y, Morehouse C, Zhu W, Sebastian Y, Czapiga M, Oganesyan V, Fu H, Niu Y, Zhang W, Streicher K, Tice D, Zhao H, Zhu M, Xu L, Herbst R, Su X, Gu Y, Li S, Huang L, Gu J, Han B, Jallal B, Shen H, Yao Y - PLoS Genet. (2016)

SRSF1 CN gain and mRNA expression correlates with survival.A: The time-to-event analysis schema with available patient specimens. In the time-to-event analyses, 96 Chinese primary SCLC patients with clinical outcome were divided into training and test cohorts according to the availabilities of matched normal, RNAseq and survival outcome information. The training set includes 22 patients with each patient having tumor and normal WES data and survival outcome. The test set includes 74 patient tumors only. Each patient has WES data from tumor and survival outcome. Among those patients, 48 patients have WES, RNAseq data, and survival outcome. b) SRSF1 mRNA expression in CN gain group and no CN gain group (p = Welch’s t-test). c) Kaplan-Meier (KM) curves comparing survival between SRSF1 low and high mRNA expression groups (n = 48). Similarly, KM curves used to evaluate the difference of survival between different SRSF1 CN statuses in d) discovery set (n = 22), e) validation set (n = 74), and f) combination of discovery set and validation set (n = 96). p* = log-rank test; p = Cox PH regression model; HR = hazard ratio.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836692&req=5

pgen.1005895.g003: SRSF1 CN gain and mRNA expression correlates with survival.A: The time-to-event analysis schema with available patient specimens. In the time-to-event analyses, 96 Chinese primary SCLC patients with clinical outcome were divided into training and test cohorts according to the availabilities of matched normal, RNAseq and survival outcome information. The training set includes 22 patients with each patient having tumor and normal WES data and survival outcome. The test set includes 74 patient tumors only. Each patient has WES data from tumor and survival outcome. Among those patients, 48 patients have WES, RNAseq data, and survival outcome. b) SRSF1 mRNA expression in CN gain group and no CN gain group (p = Welch’s t-test). c) Kaplan-Meier (KM) curves comparing survival between SRSF1 low and high mRNA expression groups (n = 48). Similarly, KM curves used to evaluate the difference of survival between different SRSF1 CN statuses in d) discovery set (n = 22), e) validation set (n = 74), and f) combination of discovery set and validation set (n = 96). p* = log-rank test; p = Cox PH regression model; HR = hazard ratio.
Mentions: Somatic copy number variants (CNVs) were identified from exome-sequencing data. Our results confirmed key oncogenic genes with recurrent CN gains/amplifications that were previously reported in SCLC [3, 5, 15,16,17], including MYC (8%), KIT (16%), and SOX2 (67%). Significant copy number gains or amplifications were observed across a cluster on chromosome 3q26-29 [5] (S5 Table). Genes with CN losses previously reported in SCLC [2, 4, 5] include RB1 (34%), RASSF1 (57%), FHIT (54%), KIF2A (16%), and PTEN (13%). A long segment along chromosome 3p22 was also detected to have significant CN loss. Recurrence rates of these genes affected by CNVs were comparable to those reported previously [3, 5]. In addition, we found recurrent gains of SRSF1 (50%) as well as concordant over-expression of mRNA for those patients with gains (p = 0.005; two-tailed two-sided Welch’s t-test; Fig 3A). Among these 96 Chinese patients, 28% had both CN gain and mRNA over-expression of SRSF1; in an independent cohort of 25 Caucasian SCLC patients (commercially purchased specimens–see Methods), we identified 32% with the same result. Further, SRSF1 CN gain was determined to be 30% (8/27 SCLC patients) in a re-analysis of the available WES data published from a previous Caucasian SCLC patient cohort–a result very similar between both Caucasian SCLC cohorts [3]. CN gains/amplifications or losses and somatic SNVs for relevant genes are summarized in S1 Fig.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

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.

Show MeSH
Related in: MedlinePlus