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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

Top mutated DNA polymerases and mutation prevalence in Fanconi anemia pathway genes in SCLC.a) Schematic representation of amino acid changes in human POLG, POLD1, POLQ proteins; b) the amino acid alterations in human POLG catalytic domain. Mutations were mapped onto the structure of human POLG using PDB Id entry 3IKM as template [6]. c) Relevant amino acid alterations in POLD1. Mutations in human POLD1 gene were mapped onto structure of the yeast DNA polymerase subunit δ using PDB entry 3IAY Orange colored ribbon represents exonuclease domain, blue colored ribbon corresponds to polymerase domain, and the green ribbon represents the N-terminal portion of the protein [27]. The mutations in both structures are shown in red spheres. d) Mutation prevalence in Fanconi anemia pathway genes.
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pgen.1005895.g002: Top mutated DNA polymerases and mutation prevalence in Fanconi anemia pathway genes in SCLC.a) Schematic representation of amino acid changes in human POLG, POLD1, POLQ proteins; b) the amino acid alterations in human POLG catalytic domain. Mutations were mapped onto the structure of human POLG using PDB Id entry 3IKM as template [6]. c) Relevant amino acid alterations in POLD1. Mutations in human POLD1 gene were mapped onto structure of the yeast DNA polymerase subunit δ using PDB entry 3IAY Orange colored ribbon represents exonuclease domain, blue colored ribbon corresponds to polymerase domain, and the green ribbon represents the N-terminal portion of the protein [27]. The mutations in both structures are shown in red spheres. d) Mutation prevalence in Fanconi anemia pathway genes.

Mentions: To better understand the genetic basis of chemo sensitivity and resistance in SCLC, we systematically surveyed SNVs and indels in all known DNA repair genes [12]. Eighty-seven percent (87%) of patients harbored ≥1 nonsilent somatic SNV in a DNA repair gene besides TP53 (S4 Table); similarly, within a Japanese SCLC study cohort in a previous study, 69% of patients were identified by the same criterion [5]. The patient prevalence of nonsilent somatic SNVs in genes classified as mismatch repair (MMR), nucleotide excision repair (NER), homologous recombination, or DNA polymerase were 22%, 30%, 26% and 35%, respectively. Twelve percent of patients harbored nonsilent somatic SNVs in DNA polymerase genes that are involved in DNA replication in NER and MMR (POLD1 and POLE, [13]). POD1, POLG and POLQ were most recurrently mutated among the 15 DNA polymerase genes. These somatic SNVs cause protein truncations and amino acid changes in the polymerase, exonuclease, and helicase domains (Fig 2A–2C). Fanconi anemia pathway genes were most recurrent with prevalence of 36%. Within this specific pathway, multiple genes involved in DNA inter-strand crosslink repair such as FANCM (7%) and BRIP1/FANCJ (7%) were among the most mutated (Fig 2D). Finally, 29% of patients harbored nonsilent somatic SNVs in genes that affect sensitivity of mammalian cells to topoisomerase inhibitors, in addition to TP53 [14].


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)

Top mutated DNA polymerases and mutation prevalence in Fanconi anemia pathway genes in SCLC.a) Schematic representation of amino acid changes in human POLG, POLD1, POLQ proteins; b) the amino acid alterations in human POLG catalytic domain. Mutations were mapped onto the structure of human POLG using PDB Id entry 3IKM as template [6]. c) Relevant amino acid alterations in POLD1. Mutations in human POLD1 gene were mapped onto structure of the yeast DNA polymerase subunit δ using PDB entry 3IAY Orange colored ribbon represents exonuclease domain, blue colored ribbon corresponds to polymerase domain, and the green ribbon represents the N-terminal portion of the protein [27]. The mutations in both structures are shown in red spheres. d) Mutation prevalence in Fanconi anemia pathway genes.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1005895.g002: Top mutated DNA polymerases and mutation prevalence in Fanconi anemia pathway genes in SCLC.a) Schematic representation of amino acid changes in human POLG, POLD1, POLQ proteins; b) the amino acid alterations in human POLG catalytic domain. Mutations were mapped onto the structure of human POLG using PDB Id entry 3IKM as template [6]. c) Relevant amino acid alterations in POLD1. Mutations in human POLD1 gene were mapped onto structure of the yeast DNA polymerase subunit δ using PDB entry 3IAY Orange colored ribbon represents exonuclease domain, blue colored ribbon corresponds to polymerase domain, and the green ribbon represents the N-terminal portion of the protein [27]. The mutations in both structures are shown in red spheres. d) Mutation prevalence in Fanconi anemia pathway genes.
Mentions: To better understand the genetic basis of chemo sensitivity and resistance in SCLC, we systematically surveyed SNVs and indels in all known DNA repair genes [12]. Eighty-seven percent (87%) of patients harbored ≥1 nonsilent somatic SNV in a DNA repair gene besides TP53 (S4 Table); similarly, within a Japanese SCLC study cohort in a previous study, 69% of patients were identified by the same criterion [5]. The patient prevalence of nonsilent somatic SNVs in genes classified as mismatch repair (MMR), nucleotide excision repair (NER), homologous recombination, or DNA polymerase were 22%, 30%, 26% and 35%, respectively. Twelve percent of patients harbored nonsilent somatic SNVs in DNA polymerase genes that are involved in DNA replication in NER and MMR (POLD1 and POLE, [13]). POD1, POLG and POLQ were most recurrently mutated among the 15 DNA polymerase genes. These somatic SNVs cause protein truncations and amino acid changes in the polymerase, exonuclease, and helicase domains (Fig 2A–2C). Fanconi anemia pathway genes were most recurrent with prevalence of 36%. Within this specific pathway, multiple genes involved in DNA inter-strand crosslink repair such as FANCM (7%) and BRIP1/FANCJ (7%) were among the most mutated (Fig 2D). Finally, 29% of patients harbored nonsilent somatic SNVs in genes that affect sensitivity of mammalian cells to topoisomerase inhibitors, in addition to TP53 [14].

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