title: Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes.
abstract: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases.
  
  
  
  We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors.
  
  
  
  We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01).
  
  
  
  We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Departments of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Serie
authors.affiliation: Cancer Biology, Mayo Clinic, Jacksonville, USA.
authors.forename: M
authors.initials: M
authors.lastname: Parasramka
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, NY, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Cheville
authors.affiliation: Computational Oncology, Sage Bionetworks, Seattle, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Bot
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Pathology, Medical College of Hebei University of Engineering, Handan, Hebei Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Departments of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hilton
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Leibovich
authors.affiliation: Departments of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Department of Pathology, Medical College of Hebei University of Engineering, Handan, Hebei Province, China.
authors.forename: J E
authors.initials: JE
authors.lastname: Eckel-Passow
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D058575:Decorin / Q000235:genetics*; D018572:Disease-Free Survival; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics*; D007797:Laminin / Q000235:genetics*; D000071234:Lumican / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000098552:Slit Homolog 2 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; C546878:DCN protein, human; D058575:Decorin; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C502335:LMO3 protein, human; C000604306:LUM protein, human; D007797:Laminin; D000071234:Lumican; D009419:Nerve Tissue Proteins; C102645:laminin alpha 2; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human; D000098552:Slit Homolog 2 Protein
keywords: extracellular matrix; metastases; renal cell carcinoma