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

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.

[1]  Martin Vingron,et al.  Comprehensive genomic profiles of small cell lung cancer , 2015, Nature.

[2]  C. Rudin,et al.  Small Cell Lung Cancer: Will Recent Progress Lead to Improved Outcomes? , 2015, Clinical Cancer Research.

[3]  F. Hirsch,et al.  Fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. , 2015, The oncologist.

[4]  Hironobu Ohmatsu,et al.  Therapeutic Priority of the PI3K/AKT/mTOR Pathway in Small Cell Lung Cancers as Revealed by a Comprehensive Genomic Analysis , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[5]  Chang Yu,et al.  Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer , 2014, Gut.

[6]  R. Yelensky,et al.  Identifying ALK rearrangements that are not detected by FISH with targeted next-generation sequencing of lung carcinoma. , 2014 .

[7]  A. Krainer,et al.  Emerging Functions of SRSF1, Splicing Factor and Oncoprotein, in RNA Metabolism and Cancer , 2014, Molecular Cancer Research.

[8]  Taofeek K Owonikoko,et al.  Small cell lung cancer: therapies and targets. , 2014, Seminars in oncology.

[9]  Duhee Bang,et al.  Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers , 2014, Genome Medicine.

[10]  L. Zender,et al.  RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation. , 2013, Carcinogenesis.

[11]  Huanming Yang,et al.  Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation , 2013, Nature Genetics.

[12]  A. Sivachenko,et al.  Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples , 2013, Nature Biotechnology.

[13]  A. Krainer,et al.  S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. , 2013, Cell reports.

[14]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer-associated genes , 2013 .

[15]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[16]  H. Gautrey,et al.  Regulation of Mcl-1 by SRSF1 and SRSF5 in Cancer Cells , 2012, PloS one.

[17]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[18]  K. Cibulskis,et al.  Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer , 2012, Nature Genetics.

[19]  Robert Gentleman,et al.  Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer , 2012, Nature Genetics.

[20]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[21]  A. Krainer,et al.  Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. , 2012, Cell reports.

[22]  A. Girstun,et al.  Activities of topoisomerase I in its complex with SRSF1. , 2012, Biochemistry.

[23]  A. Krainer,et al.  THE SPLICING FACTOR SRSF1 REGULATES APOPTOSIS AND PROLIFERATION TO PROMOTE MAMMARY EPITHELIAL CELL TRANSFORMATION , 2011, Nature Structural &Molecular Biology.

[24]  John Quackenbush,et al.  Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV , 2011, Bioinform..

[25]  Stephen J. Salipante,et al.  Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers , 2011, Proceedings of the National Academy of Sciences.

[26]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[27]  R. Wood,et al.  DNA polymerases and cancer , 2011, Nature Reviews Cancer.

[28]  Richard Simon,et al.  Identifying cancer driver genes in tumor genome sequencing studies , 2011, Bioinform..

[29]  M. Pietanza,et al.  小细胞肺癌的的分子发病机制 , 2010, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[30]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[31]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[32]  M. Pietanza,et al.  The molecular pathogenesis of small cell lung cancer , 2010, Cancer biology & therapy.

[33]  T. Hyslop,et al.  Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. , 2010, Cancer research.

[34]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[35]  Yves Pommier,et al.  Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription , 2010, Nature Cell Biology.

[36]  Y. Yin,et al.  Structural Insight into Processive Human Mitochondrial DNA Synthesis and Disease-Related Polymerase Mutations , 2009, Cell.

[37]  Y. Yin,et al.  Structural Insight into Processive Human Mitochondrial DNA Synthesis and Disease-Related Polymerase Mutations , 2009, Cell.

[38]  Robert E. Johnson,et al.  Structural basis of high fidelity DNA synthesis by yeast DNA polymerase delta , 2009, Nature Structural &Molecular Biology.

[39]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[40]  Y. Hayashi,et al.  FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non‐Hodgkin lymphoma , 2009, British journal of haematology.

[41]  J. Cigudosa,et al.  The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. , 2009, Human molecular genetics.

[42]  A. Ferrando,et al.  The role of NOTCH1 signaling in T-ALL. , 2009, Hematology. American Society of Hematology. Education Program.

[43]  A. Ferrando.  The role of NOTCH 1 signaling in TALL , 2009 .

[44]  F. Rojo,et al.  Genetic changes in small cell lung carcinoma , 2008, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[45]  A. Krainer,et al.  The gene encoding the splicing factor SF2/ASF is a proto-oncogene , 2007, Nature Structural &Molecular Biology.

[46]  Y. Pommier.  Topoisomerase I inhibitors: camptothecins and beyond , 2006, Nature Reviews Cancer.

[47]  S. Howell,et al.  DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance , 2006, Molecular Cancer Therapeutics.

[48]  Tomas Lindahl,et al.  Human DNA repair genes, 2005. , 2005, Mutation research.

[49]  Elisa Rossi,et al.  Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. , 2005, Journal of the National Cancer Institute.

[50]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[51]  C. Stevens,et al.  Chk2 activates E2F-1 in response to DNA damage , 2003, Nature Cell Biology.

[52]  G. Kalemkerian,et al.  Small cell lung cancer , 2010, Seminars in Respiratory and Critical Care Medicine.

[53]  E. Rogakou,et al.  Quantitative Detection of 125IdU-Induced DNA Double-Strand Breaks with γ-H2AX Antibody , 2002 .

[54]  E. Rogakou,et al.  Quantitative detection of (125)IdU-induced DNA double-strand breaks with gamma-H2AX antibody. , 2002, Radiation research.

[55]  Richard D. Wood,et al.  Human DNA Repair Genes , 2001, Science.

[56]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[57]  F. van Roy,et al.  The human cadherin‐10 gene: complete coding sequence, predominant expression in the brain, and mapping on chromosome 5p13–14 , 1999, FEBS letters.

[58]  S. Parodi,et al.  Mechanism of resistance to cisplatin in a human ovarian‐carcinoma cell line selected for resistance to doxorubicin: Possible role of p53 , 1997, International journal of cancer.

[59]  R. Brown,et al.  Cisplatin, camptothecin, and taxol sensitivities of cells with p53-associated multidrug resistance. , 1996, Molecular pharmacology.

[60]  D. Housman,et al.  p53-dependent apoptosis modulates the cytotoxicity of anticancer agents , 1993, Cell.

[61]  J. Manley,et al.  A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro , 1990, Cell.

[62]  A. Auerbach.  A test for Fanconi's anemia [letter] , 1988 .

[63]  A. Auerbach.  A test for Fanconi's anemia. , 1988, Blood.