title: Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma.
abstract: BACKGROUND
  Dystroglycan (DG) is a cell-surface laminin receptor that links the cytoskeleton to the extracellular matrix in a variety of epithelial tissues. Its function as a matrix receptor requires extensive glycosylation of its extracellular subunit αDG, which involves at least 13 distinct genes. Prior work has shown loss of αDG glycosylation in an assortment of carcinomas, including clear cell renal cell carcinoma (ccRCC) though the cause (s) and functional consequences of this loss are still unclear.
  
  
  METHODS
  Using The Cancer Genome Atlas (TCGA) database, we analyzed the DG glycosylation pathway to identify changes in mRNA expression and correlation with clinical outcomes. We validated our findings with a cohort of 65 patients treated with radical nephrectomy by analyzing DG glycosylation via immunohistochemistry and gene expression via qRT-PCR.
  
  
  RESULTS
  Analysis of TCGA database revealed frequent dysregulation of a subset of DG glycosyltransferases. Most notably, there was a frequent, significant downregulation of GYLTL1B (LARGE2) and ISPD. DG glycosylation is frequently impaired in ccRCC patient samples and most strongly associates with downregulation of GYLTL1B.
  
  
  CONCLUSIONS
  Reduced levels of GYLTL1B and ISPD mRNA associated with increased patient mortality and are the likely cause of αDG hypoglycosylation in ccRCC.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa, USA.
authors.forename: Deqin
authors.initials: D
authors.lastname: Ma
authors.affiliation: Institute for Clinical and Translational Sciences, Iowa, USA.
authors.forename: James
authors.initials: J
authors.lastname: Schappet
authors.affiliation: Department of Biostatistics, University of Iowa Carver College of Medicine, Iowa, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Breheny
authors.affiliation: Holden Comprehensive Cancer Center, Iowa, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mott
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bannick
authors.affiliation: Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Askeland
authors.affiliation: Holden Comprehensive Cancer Center, Iowa, USA.|Department of Urology, University of Iowa Carver College of Medicine, Iowa, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, 6-510 Bowen Science Bldg, Iowa, USA. michael-henry@uiowa.edu.|Department of Pathology, University of Iowa Carver College of Medicine, Iowa, USA. michael-henry@uiowa.edu.|Holden Comprehensive Cancer Center, Iowa, USA. michael-henry@uiowa.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D019295:Computational Biology; D019175:DNA Methylation; D030541:Databases, Genetic; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D016695:Glycosyltransferases; C500430:LARGE2 protein, human; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human