title: An integrative genomics approach for identifying novel functional consequences of PBRM1 truncated mutations in clear cell renal cell carcinoma (ccRCC).
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Recent large-scale next-generation sequencing analyses reveal that PBRM1 is the second most frequently mutated gene harboring many truncated mutations and has a suspected tumor suppressor role in ccRCC. However, the biological consequences of PBRM1 somatic mutations (e.g., truncated mutations) that drive tumor progression in ccRCC remain unclear.
  
  
  
  In this study, we proposed an integrative genomics approach to explore the functional consequences of PBRM1 truncated mutations in ccRCC by incorporating somatic mutations, mRNA expression, DNA methylation, and microRNA (miRNA) expression profiles from The Cancer Genome Atlas (TCGA). We performed a systematic analysis to detect the differential molecular features in a total of 11 ccRCC samples harboring PBRM1 truncated mutations from the 33 "pan-negative" ccRCC samples. We excluded the samples that had any of the five high-confidence driver genes (VHL, BAP1, SETD2, PTEN and KDM5C) reported in ccRCC to avoid their possible influence in our results.
  
  
  
  We identified 613 differentially expressed genes (128 up-regulated and 485 down-regulated genes using cutoff |log2FC| > 1 and p < 0.05) in PBRM1 mutated group versus "pan-negative" group. The gene function enrichment analysis revealed that down-regulated genes were significantly enriched in extracellular matrix organization (adjusted p = 2.05 × 10(-7)), cell adhesion (adjusted p = 2.85 × 10(-7)), and ion transport (adjusted p = 9.97 × 10(-6)). Surprisingly, 26 transcriptional factors (TFs) genes including HOXB9, PAX6 and FOXC1 were found to be significantly differentially expressed (23 over expressed TFs and three lower expressed TFs) in PBRM1 mutated group compared with "pan-negative" group. In addition, we identified 1405 differentially methylated CpG sites (targeting 1308 genes, ||log2FC| > 1, p < 0.01) and 185 significantly altered microRNAs (|log2FC| > 1, p < 0.05) associated with truncated PBRM1 mutations. Our integrative analysis suggested that methylation and miRNA alterations were likely the downstream events associated with PBRM1 truncation mutations.
  
  
  
  In summary, this study provided some important insights into the understanding of tumorigenesis driven by PBRM1 truncated mutations in ccRCC. The approach may be applied to many driver genes in various cancers.
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA.|Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bray
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA. zhongming.zhao@uth.tmc.edu.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. zhongming.zhao@uth.tmc.edu.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, 37212, USA. zhongming.zhao@uth.tmc.edu.|Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. zhongming.zhao@uth.tmc.edu.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors
keywords: Clear cell renal cell carcinoma (ccRCC); Driver gene; Expression; Methylation; PBRM1; microRNA