title: Integrative bioinformatics analysis reveals new prognostic biomarkers of clear cell renal cell carcinoma.
abstract: BACKGROUND
  The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome.
  
  
  METHODS
  To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown.
  
  
  RESULTS
  After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P < 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P < 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro.
  
  
  CONCLUSIONS
  Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada;
authors.forename: Henriett
authors.initials: H
authors.lastname: Butz
authors.affiliation: Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Szabó
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Roy
authors.initials: R
authors.lastname: Nofech-Mozes
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Fabio
authors.initials: F
authors.lastname: Rotondo
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Kalman
authors.initials: K
authors.lastname: Kovacs
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Lorna
authors.initials: L
authors.lastname: Mirham
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Hala
authors.initials: H
authors.lastname: Girgis
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada;
authors.forename: Dina
authors.initials: D
authors.lastname: Boles
authors.affiliation: HAS-SE "Lendulet" Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.affiliation: Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; yousefg@smh.ca.
authors.forename: George M
authors.initials: GM
authors.lastname: Yousef
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods* / Q000706:statistics & numerical data; D004268:DNA-Binding Proteins / Q000235:genetics; D003627:Data Interpretation, Statistical; D030541:Databases, Genetic; D042241:Early Diagnosis; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D035683:MicroRNAs; C425208:PCLAF protein, human; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors