title: Characterization of long non-coding RNA transcriptome in clear-cell renal cell carcinoma by next-generation deep sequencing.
abstract: BACKGROUND
  Long non-coding RNA (lncRNA) have proven to play key roles in cell physiology from nuclear organization and epigenetic remodeling to post-transcriptional regulation. Last decade, gene expression based-classifications have been developed in clear-cell renal cell carcinoma (ccRCC) to identify distinct subtypes of disease and predict patient's outcome. However, there are no current lncRNA comprehensive characterizations in ccRCC.
  
  
  METHODS
  RNA-sequencing profiles of 475 primary ccRCC samples from the Cancer Genome Atlas (TCGA) were used to assess expressed lncRNA and identify lncRNA-based classification. In addition, integrative analysis was performed to correlate tumor subtypes with copy-number alterations and somatic mutations.
  
  
  RESULTS
  Using stringent criteria, we identified 1934 expressed lncRNA and assessed their chromatin marks. Unsupervised clustering unravels four lncRNA subclasses in ccRCC associated with distinct clinicopathological and genomic features of this disease. Cluster C2 (23.4%) defines the most aggressive tumours, with the highest Fuhrman grade and stage and the worst overall survival time. Furthermore, cluster C2 is enriched for 9p deletion and chromatin remodeler BAP1 somatic mutations. Interestingly, cluster C4 (7.8%) is related to a tumor subtype arising from the distal tubules of the nephron. Consistent with its distinct ontogeny, cluster C4 is devoid of classical alterations seen in ccRCC, bears frequent 1p deletion and 17q gain, and is enriched for MiTF/TFE translocations. In addition, reexaminations of copy-number data from one side and tumor histology by pathologists from the other side reveal misclassified tumors within C4 cluster including chromophobe RCC and clear cell papillary RCC.
  
  
  CONCLUSIONS
  This study establishes a foundation for categorizing lncRNA subclasses, which may contribute to understand tumor ontogeny and help predicting patients' outcome in ccRCC.
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France. Electronic address: gabriel.malouf@psl.aphp.fr.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Compérat
authors.affiliation: Department of Urology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Rouprêt
authors.affiliation: Department of Urology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cussenot
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Thompson
authors.affiliation: Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), GRC5, ONCOTYPE-Uro, Institut Universitaire de Cancérologie, Assistance-Publique Hôpitaux de Paris, 75013, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Spano
authors.affiliation: Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: xsu1@mdanderson.org.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D030561:Databases, Nucleic Acid; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate
chemical_list: D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm
keywords: Expression profiling; Genomic aberrations; Histone markers; Long non-coding RNA; RNA-Seq; ccRCC