title: Long non-coding RNA profiling links subgroup classification of endometrioid endometrial carcinomas with trithorax and polycomb complex aberrations.
abstract: BACKGROUND
  Integrative analysis of endometrioid endometrial carcinoma (EEC) using multiple platforms has distinguished four molecular subgroups. However, the landscape of expressed long non-coding RNAs (lncRNA) and their role in charting EEC subgroups and determining clinical aggressiveness remain largely unknown.
  
  
  RESULTS
  Using stringent criteria, we identified 1,931 expressed lncRNAs and predicted potential drivers through integrative analysis. Unsupervised clustering of lncRNA expression revealed three robust categories: basal-like, luminal-like and CTNNB1-enriched subgroups. Basal-like subgroup was enriched for aggressive tumors with higher pathological grade (p < 0.0001), TNM stage (p = 0.01), and somatic mutations in trithorax-group genes (MLL, MLL2 and MLL3); and it overexpressed polycomb genes EZH2 and CBX2. In contrast to the luminal-like subgroup, progesterone (PGR) and estrogen receptor (ESR1) genes were highly down-regulated in the EEC basal-like subgroup. Consistent with its enrichment for CTNNB1 mutations (69%), lncRNA profile of the CTNNB1-enriched EEC subgroup was highly similar to that of the CTNNB1-enriched liver cancer subgroup.
  
  
  METHODS
  We performed integrative analysis of lncRNAs in EEC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 191 primary tumors for which genomic data were also available. We established lncRNA subgroup classification, correlated it with chromatin modifying gene expression, and described correlations between our lncRNA classification and clinico-genomic tumor features.
  
  
  CONCLUSIONS
  Our results reveal the utility of systematic characterization of clinically annotated EEC in three clinically relevant subgroups. They also highlight the convergence of aberrations in polycomb- and trithorax-group genes in aggressive basal EEC subtypes, providing a rationale for further investigation of epigenetic therapy in this setting.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Thompson
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.affiliation: Department of Biostatistics, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Spano
authors.affiliation: Department of Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000145:classification / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C570479:CBX2 protein, human; D047628:Estrogen Receptor alpha; C497422:KMT2A protein, human; D063146:Polycomb-Group Proteins; D062085:RNA, Long Noncoding; D011980:Receptors, Progesterone; D051176:beta Catenin; D051788:Myeloid-Lymphoid Leukemia Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1
keywords: RNA-Seq; endometrioid endometrial carcinoma; expression profiling; long non-coding RNA; polycomb complex