Long non-coding RNA profiling links subgroup classification of endometrioid endometrial carcinomas with trithorax and polycomb complex aberrations
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Yunyun Jiang1,*, Gabriel G. Malouf2,*, Jianping Zhang3,*, Xiaofeng Zheng3, Yunxin Chen4, Erika J. Thompson5, John N. Weinstein3, Ying Yuan6, Jean-Philippe Spano2, Russell Broaddus7, Nizar M. Tannir4, David Khayat2, Karen H. Lu1, Xiaoping Su3
1Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Cancer Center, Houston, TX, USA
2Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de Cancérologie, AP-HP, Paris, France
3Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA
4Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA
5Department of Genetics, UT MD Anderson Cancer Center, Houston, TX, USA
6Department of Biostatistics, UT MD Anderson Cancer Center, Houston, TX, USA
7Department of Pathology, UT MD Anderson Cancer Center, Houston, TX, USA
*These authors have contributed equally to this work
Karen H. Lu, e-mail: firstname.lastname@example.org
Xiaoping Su, e-mail: email@example.com
Keywords: endometrioid endometrial carcinoma, long non-coding RNA, RNA-Seq, expression profiling, polycomb complex
Received: August 06, 2015 Accepted: August 29, 2015 Published: September 26, 2015
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.
Materials and 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.
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.
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.
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