Abstract 161: Long noncoding RNA subtype classification of human prostate adenocarcinomas
Authors: Malouf Gabriel G. , Zhang Jianping , Spano Jean-Philippe , Compérat Eva , Tannir Nizar M. , Thompson Erika K. , Weinstein John N. , Tripathy Debasish , Khayat David , Su Xiaoping 
Published: August 2015

Abstract
Background: Long non-coding RNAs (lncRNAs) play a key role in regulating normal cell physiology as well as cancer progression. Although the role of several lncRNAs has been established in prostate cancer progression, the subtype classification of lncRNAs in human prostate cancer adenocarcinomas remains fully uncovered.
Material and Methods: We performed a genomic analysis of GENCODE lncRNAs in prostate adenocarcinoma (PRAD), using The Cancer Genome Atlas (TCGA) RNA-Seq profiles of 297 primary tumors. Furthermore, we described global correlations between lncRNAs and expression of cis-acting genes, and established lncRNAs expression-based subtypes with distinct signatures. In addition, lncRNAs expression-based subtypes were correlated with copy-number alterations and somatic mutations.
Results: Using stringent criteria, we identified 1,596 lncRNAs and predicted those that are potential drivers for cancer progression through integrative analysis. The expression of 885 (55.4%) lncRNAs showed a significantly positive correlation with the mRNAs expression of their neighboring genes, while only 29 (1.8%) lncRNAs showed a significantly negative correlation. 511 lncRNAs were significantly differentially expressed between PRAD and normal prostate; GREAT analysis showed that those lncRNAs are cis-acting on genes involved in the establishment of apical/basal cell polarity (p = 3.5×10−6). Unsupervised clustering of cancer differentially expressed lncRNAs revealed three robust subtypes, which were highly related with ERG gene fusions status (p = 2.2×10-16). While C2 cluster (n = 125) was composed of 76.3% of PRAD with ERG gene fusions cluster (n = 127), C1 cluster was composed in majority of PRAD without ERG gene fusions (83.5%). Cluster C3 (n = 45) stood out as a unique cluster with only 35% of PRAD samples bearing ERG fusions. Of note, those 3 subtypes were not different according to TNM stage, Gleason grade and age. Intriguingly, only SPOP somatic mutation was found to be enriched in C1 cluster (p = 7.9×10-6). Using copy number changes, we identified 13 regions which were differentially deleted between the three subgroups, including chr21q22.3 and chr8p21.3. As expected, Gene set enrichment analysis (GSEA) revealed enrichment of C2 cluster with prostate cancer TMPRSS2_ERG fusion signature, while C1 cluster was enriched for PPAR (p&lt;10−12) and breast cancer ESR1 signatures (p&lt;10−12). Importantly, Cluster 3 was enriched for EZH2 targets (p = 0.004) suggesting efficacy of EZH2 inhibitors in this subgroup. Finally, C3 cluster showed activation of UXT (Androgen receptor Trapped clone 27 protein) pathway (p = 2.73×10−3).
Conclusion: This study characterizes the spectrum of lncRNAs, which may be important in normal prostate as well as in prostate adenocarcinomas. Furthermore, we establish the foundation of lncRNAs expression-based subtype classification in human prostate adenocarcinomas.
Citation Format: Gabriel G. Malouf, Jianping Zhang, Jean-Philippe Spano, Eva Compérat, Nizar M. Tannir, Erika K. Thompson, John N. Weinstein, Debasish Tripathy, David Khayat, Xiaoping Su. Long noncoding RNA subtype classification of human prostate adenocarcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2015-161