A long non-coding RNA signature to improve prognosis prediction of gastric cancer

BackgroundIncreasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed at developing alncRNA signature to improve prognosis prediction of gastric cancer (GC).MethodsUsing a lncRNA-mining approach, we performed lncRNA expression profiling in large GC cohorts from Gene Expression Ominus (GEO), including GSE62254 data set (N = 300) and GSE15459 data set (N = 192). We established a set of 24-lncRNAs that were significantly associated with the disease free survival (DFS) in the test series.ResultsBased on this 24-lncRNA signature, the test series patients could be classified into high-risk or low-risk subgroup with significantly different DFS (HR = 1.19, 95 % CI = 1.13–1.25, P < 0.0001). The prognostic value of this 24-lncRNA signature was confirmed in the internal validation series and another external validation series, respectively. Further analysis revealed that the prognostic value of this signature was independent of lymph node ratio (LNR) and postoperative chemotherapy. Gene set enrichment analysis (GSEA) indicated that high risk score group was associated with several cancer recurrence and metastasis associated pathways.ConclusionsThe identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GC biogenesis. Our results may provide an efficient classification tool for clinical prognosis evaluation of GC.

[1]  W. Lam,et al.  Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer , 2014, Oncotarget.

[2]  Nazneen Rahman,et al.  Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. , 2008, The New England journal of medicine.

[3]  Ahmedin Jemal,et al.  Global Cancer Incidence and Mortality Rates and Trends—An Update , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[4]  L. Gianni,et al.  Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses. , 2002, Tumori.

[5]  H. Grabsch,et al.  FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study , 2014, British Journal of Cancer.

[6]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[7]  Guojun Zhang,et al.  High expression of polo-like kinase 1 is associated with the metastasis and recurrence in urothelial carcinoma of bladder. , 2013, Urologic oncology.

[8]  R. Biamonte,et al.  De Gramont Schedule is a Very Low Toxic and Effective Regimen in Low Performance Status Patients Affected by Metastatic Gastric Cancer: Preliminary Report , 2002, Tumori.

[9]  Yunli Zhou,et al.  Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. , 2010, Endocrinology.

[10]  A. Jimeno,et al.  HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Tomohiro Osaki,et al.  Prognostic significance of the ratio between metastatic and dissected lymph nodes (n ratio) in patients with advanced gastric cancer , 2008, Journal of surgical oncology.

[12]  R. Labianca,et al.  The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[13]  L. Lipovich,et al.  Identification of long noncoding RNAs dysregulated in the midbrain of human cocaine abusers , 2015, Journal of neurochemistry.

[14]  H. Ishwaran.  Variable importance in binary regression trees and forests , 2007, 0711.2434.

[15]  Xiulong Ma,et al.  Downregulation of the long non-coding RNA TUSC7 promotes NSCLC cell proliferation and correlates with poor prognosis. , 2016, American journal of translational research.

[16]  T. Gambichler,et al.  Long-noncoding RNAs in basal cell carcinoma , 2016, Tumor Biology.

[17]  K. Yamashita,et al.  Lymph node ratio is a critical prognostic predictor in gastric cancer treated with S-1 chemotherapy , 2013, Gastric Cancer.

[18]  B. Son,et al.  Prognostic Significance of the Metastatic Lymph Node Ratio in Patients with Gastric Cancer , 2012, World Journal of Surgery.

[19]  G. Sachs,et al.  C6orf176: a novel possible regulator of cAMP-mediated gene expression. , 2012, Physiological genomics.

[20]  M. Orditura,et al.  Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients , 2007, Annals of Surgical Oncology.

[21]  H. Espejo,et al.  [Gastric cancer]. , 1996, Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru.

[22]  J. Zhao,et al.  Long non-coding RNA Linc00152 is involved in cell cycle arrest, apoptosis, epithelial to mesenchymal transition, cell migration and invasion in gastric cancer , 2015, Cell cycle.

[23]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[24]  Xiaoqin Zhang,et al.  A long non-coding RNA signature in glioblastoma multiforme predicts survival , 2013, Neurobiology of Disease.

[25]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[26]  Hsiang-Cheng Chi,et al.  Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. , 2014, World journal of gastroenterology.

[27]  Carolyn J. Brown,et al.  The functional role of long non-coding RNA in human carcinomas , 2011, Molecular Cancer.

[28]  E. Oki,et al.  Gastric Cancer Patients with High PLK1 Expression and DNA Aneuploidy Correlate with Poor Prognosis , 2016, Oncology.

[29]  A. D’Andrea,et al.  A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy , 2012, Journal of the National Cancer Institute.

[30]  Leonard Lipovich,et al.  MacroRNA underdogs in a microRNA world: evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA. , 2010, Biochimica et biophysica acta.

[31]  Neal P. Kawas,et al.  The CASC15 long intergenic non-coding RNA locus is involved in melanoma progression and phenotype-switching , 2015, The Journal of investigative dermatology.

[32]  Hemant Ishwaran,et al.  The effect of splitting on random forests , 2014, Machine Learning.

[33]  Hyun Cheol Chung,et al.  Oncogenic Pathway Combinations Predict Clinical Prognosis in Gastric Cancer , 2009, PLoS genetics.

[34]  I. Seim,et al.  Complex organisation and structure of the ghrelin antisense strand gene GHRLOS, a candidate non-coding RNA gene , 2008, BMC Molecular Biology.

[35]  Shu-Kay Ng,et al.  Relationship of XIST expression and responses of ovarian cancer to chemotherapy. , 2002, Molecular cancer therapeutics.

[36]  G. Esposito,et al.  Comparison of the 6th and 7th editions of the AJCC/UICC TNM staging system for gastric cancer focusing on the “N” parameter-related survival: the monoinstitutional NodUs Italian study , 2015, World Journal of Surgical Oncology.

[37]  Jason G. Jin,et al.  Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes , 2015, Nature Medicine.

[38]  Shuhan Sun,et al.  Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans , 2011, Hepatology.

[39]  Y. Sugiyama,et al.  Prognostic Significance of the Metastatic Lymph Node Ratio in Gastric Cancer Patients , 2009, World Journal of Surgery.

[40]  L. Kiemeney,et al.  DD3PCA3-based Molecular Urine Analysis for the Diagnosis of Prostate Cancer , 2003 .

[41]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[42]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[43]  W. De,et al.  Decreased long noncoding RNA MIR31HG is correlated with poor prognosis and contributes to cell proliferation in gastric cancer , 2016, Tumor Biology.

[44]  Ji-Long Liu,et al.  Non-coding RNA LINC00473 mediates decidualization of human endometrial stromal cells in response to cAMP signaling , 2016, Scientific Reports.

[45]  Y. Fujii,et al.  Gene Expression Signature–Based Prognostic Risk Score in Patients with Primary Central Nervous System Lymphoma , 2012, Clinical Cancer Research.

[46]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[47]  Liangdan Sun,et al.  Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus , 2015, Arthritis Research & Therapy.

[48]  Anderson Chun On Tsang,et al.  Long non-coding RNA expression profiles predict clinical phenotypes in glioma , 2012, Neurobiology of Disease.

[49]  Xiang Du,et al.  The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine , 2013, Modern Pathology.

[50]  Y. Kodera,et al.  Efficacy of Adjuvant Chemotherapy Using Oral Fluorinated Pyrimidines for Curatively Resected Gastric Cancer: A Meta-Analysis of Centrally Randomized Controlled Clinical Trials in Japan , 2006, Journal of chemotherapy.

[51]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[52]  E. İlhan,et al.  Recent developments and innovations in gastric cancer. , 2016, World journal of gastroenterology.

[53]  Joon-Oh Park,et al.  Impact of MET amplification on gastric cancer: possible roles as a novel prognostic marker and a potential therapeutic target. , 2011, Oncology reports.

[54]  W. Alexander.  ESMO World Congress on Gastrointestinal Cancer. , 2017, P & T : a peer-reviewed journal for formulary management.

[55]  Zhen Su,et al.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer , 2013 .

[56]  R. Guigó,et al.  CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis. , 2015, Journal of molecular and cellular cardiology.

[57]  S. Emmrich,et al.  LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia , 2014, Molecular Cancer.

[58]  C. Compton,et al.  The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the Future of TNM , 2010, Annals of Surgical Oncology.

[59]  J. Ji,et al.  Prognostic value of metastatic lymph node ratio as an additional tool to the TNM stage system in gastric cancer. , 2015, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[60]  Ji-Lin Wang,et al.  A long non-coding RNA signature to improve prognosis prediction of colorectal cancer , 2014, Oncotarget.

[61]  Changwen Bo,et al.  Long noncoding RNA uc.338 promotes cell proliferation through association with BMI1 in hepatocellular carcinoma , 2016, Human Cell.

[62]  F. Kaye,et al.  cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth. , 2016, The Journal of clinical investigation.

[63]  J. Ajani,et al.  Molecular biomarkers in gastric cancer. , 2015, Journal of the National Comprehensive Cancer Network : JNCCN.

[64]  John T. Wei,et al.  Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression , 2011, Nature Biotechnology.

[65]  A. Chinnaiyan,et al.  The emergence of lncRNAs in cancer biology. , 2011, Cancer discovery.

[66]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[67]  K. Yamashita,et al.  Lymph node ratio as a novel and simple prognostic factor in advanced gastric cancer. , 2016, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[68]  Wenwen Yin,et al.  Elevated E2F7 expression predicts poor prognosis in human patients with gliomas , 2016, Journal of Clinical Neuroscience.

[69]  P. Lu,et al.  Lymph Node Ratio Is an Independent Prognostic Factor in Gastric Cancer After Curative Resection (R0) Regardless of the Examined Number of Lymph Nodes , 2013, American journal of clinical oncology.

[70]  Daniel Birnbaum,et al.  Genome profiling of ERBB2-amplified breast cancers , 2010, BMC Cancer.

[71]  J. Mattick,et al.  The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. , 2011, Cancer research.

[72]  Leonard Lipovich,et al.  Erratum to "MacroRNA underdogs in a microRNA world: Evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA" [Biochem. Biophys. Acta 1799 (2010) 597-615] , 2011 .

[73]  Anirban P. Mitra,et al.  A Central Role for Long Non-Coding RNA in Cancer , 2011, Front. Gene..

[74]  Yingyi Wang,et al.  Long Noncoding RNA Profiles Reveal Three Molecular Subtypes in Glioma , 2014, CNS neuroscience & therapeutics.

[75]  Leping Li,et al.  Long noncoding RNAs as potential biomarkers in gastric cancer: Opportunities and challenges. , 2016, Cancer letters.

[76]  Yunyu Zhang,et al.  Bioinformatics analysis of microarray data. , 2009, Methods in molecular biology.

[77]  Qiang Wang,et al.  Microarray analysis of Long non-coding RNA expression profiles in human gastric cells and tissues with Helicobacter pylori Infection , 2015, BMC Medical Genomics.

[78]  Udaya B. Kogalur,et al.  High-Dimensional Variable Selection for Survival Data , 2010 .

[79]  Yingdong Zhao,et al.  Analysis of Gene Expression Data Using BRB-Array Tools , 2007, Cancer informatics.

[80]  Kun Liu,et al.  Overexpression of long noncoding RNA HOTTIP promotes tumor invasion and predicts poor prognosis in gastric cancer , 2016, OncoTargets and therapy.

[81]  J Alfred Witjes,et al.  DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. , 2003, European urology.

[82]  D. Rattner,et al.  Comparison of a Lymph Node Ratio–Based Staging System With the 7th AJCC System for Gastric Cancer: Analysis of 18,043 Patients From the SEER Database , 2012, Annals of surgery.