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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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Related in: MedlinePlus

Mutations in CDH10 associate with poor survival in Chinese SCLC patients.a) Schematic representation of amino acid consequences from mutations identified in SCLC patients in human CDH10 protein b) Kaplan-Meier (KM) curves comparing survival between patients harboring at least one nonsilent mutation in CDH10 (n = 12) and those not (n = 84).p* = log-rank test; p = Cox PH regression model; HR = hazard ratio
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pgen.1005895.g001: Mutations in CDH10 associate with poor survival in Chinese SCLC patients.a) Schematic representation of amino acid consequences from mutations identified in SCLC patients in human CDH10 protein b) Kaplan-Meier (KM) curves comparing survival between patients harboring at least one nonsilent mutation in CDH10 (n = 12) and those not (n = 84).p* = log-rank test; p = Cox PH regression model; HR = hazard ratio

Mentions: To evaluate the impact of these mutations in these three genes on patient outcomes, we used a Cox proportion hazard (PH) regression model to correlate the mutation status with survival. The patients were split into two groups: those harboring at least one nonsilent somatic mutation and those without. Among these three genes, patients with mutations in CDH10, a cadherin which is predominantly expressed in brain [11], displayed a significant association with poor survival, after adjusting for age, gender, tumor stage, and chemotherapy status (p = 0.0127). Twelve of 99 patient harbored CDH10 mutations, mostly located in the cadherin domain with high confidence protein affecting predictions (i.e. SIFT) (Fig 1).


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)

Mutations in CDH10 associate with poor survival in Chinese SCLC patients.a) Schematic representation of amino acid consequences from mutations identified in SCLC patients in human CDH10 protein b) Kaplan-Meier (KM) curves comparing survival between patients harboring at least one nonsilent mutation in CDH10 (n = 12) and those not (n = 84).p* = log-rank test; p = Cox PH regression model; HR = hazard ratio
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836692&req=5

pgen.1005895.g001: Mutations in CDH10 associate with poor survival in Chinese SCLC patients.a) Schematic representation of amino acid consequences from mutations identified in SCLC patients in human CDH10 protein b) Kaplan-Meier (KM) curves comparing survival between patients harboring at least one nonsilent mutation in CDH10 (n = 12) and those not (n = 84).p* = log-rank test; p = Cox PH regression model; HR = hazard ratio
Mentions: To evaluate the impact of these mutations in these three genes on patient outcomes, we used a Cox proportion hazard (PH) regression model to correlate the mutation status with survival. The patients were split into two groups: those harboring at least one nonsilent somatic mutation and those without. Among these three genes, patients with mutations in CDH10, a cadherin which is predominantly expressed in brain [11], displayed a significant association with poor survival, after adjusting for age, gender, tumor stage, and chemotherapy status (p = 0.0127). Twelve of 99 patient harbored CDH10 mutations, mostly located in the cadherin domain with high confidence protein affecting predictions (i.e. SIFT) (Fig 1).

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