title: A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma.
abstract: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC).
  
  
  
  Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival.
  
  
  
  CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003).
  
  
  
  CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Gremel
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Dijana
authors.initials: D
authors.lastname: Djureinovic
authors.affiliation: Department of Oncology, Radiology and Radiation Science, Uppsala University, Uppsala, Sweden.
authors.forename: Marjut
authors.initials: M
authors.lastname: Niinivirta
authors.affiliation: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK.|Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Laird
authors.affiliation: Atlas Antibodies AB, Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Ljungqvist
authors.affiliation: Atlas Antibodies AB, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Johannesson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.affiliation: Lab Surgpath, Mumbai, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Navani
authors.affiliation: Lab Surgpath, Mumbai, India.
authors.forename: Naila
authors.initials: N
authors.lastname: Khan
authors.affiliation: Lab Surgpath, Mumbai, India.
authors.forename: Tushar
authors.initials: T
authors.lastname: Patil
authors.affiliation: Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Sivertsson
authors.affiliation: Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlén
authors.affiliation: School of Medicine, University of St. Andrews, St. Andrews, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Department of Oncology, Radiology and Radiation Science, Uppsala University, Uppsala, Sweden.
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Ullenhag
authors.affiliation: Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.|Academic Urology Group, University of Cambridge, Box 43, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hill's Road, CB2 0QQ, Cambridge, UK.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Stewart
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. fredrik.ponten@igp.uu.se.|Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjölds Väg 20, SE-751 85, Uppsala, Sweden. fredrik.ponten@igp.uu.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D030541:Databases, Genetic; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor
keywords: Cubilin; Immunohistochemistry; Independent prognostic biomarker; Renal cell carcinoma