Abstract 5405: Comprehensive analysis of long non-coding RNAs in human stomach adenocarcinoma molecular subtypes
Authors: Chen Jian , Chen Jiun-Sheng , Xie Keping , Stroehlein John R , Davila Marta , Su Xiaoping 
Published: July 2017

Objective: Long non-coding RNA (lncRNA) plays key role in cell biology including epigenetic remodeling and post-transcriptional regulation. The potential roles of lncRNAs as biomarkers and therapeutic targets have been proven in solid tumors. Molecular profiling in stomach adenocarcinoma (STAD) has been characterized using The Cancer Genome Atlas (TCGA) database. However, there are no current lncRNA comprehensive analyses and the relationships between patterns of molecular subtypes and the signature of lncRNA in in human stomach adenocarcinoma are unclear.

Methods: (1) The Cancer Genome Atlas (TCGA) 312 primary STAD RNA-Seq data (bam files) and their related clinical data were obtained from the Cancer Genomics Hub and TCGA Data Portal. (2) We filtered the dataset to remove lncRNAs with low expression, defined as having an RPKM value &lt;1 in at least 90% of the tumor samples. (3) We generated a correlation matrix between lncRNAs and mRNAs by computing the Pearson correlation coefficient between all pairs of significant lncRNAs and mRNAs. A matrix was constructed with entries in the ternary scale (-1, 0, 1), where the top 1% with negative correlation was assigned -1; the top 1% with positive correlation was assigned 1; and the others were assigned 0. The matrix was clustered and visualized using a Euclidian distance metric and complete linkage clustering.

Results: (1) Using stringent criteria, we identified 1830 expressed lncRNAs in human genome in STAD. (2) Unsupervised clustering of lncRNA expression in STAD revealed five robust categories: clusters C1-C5. (3) We further performed concordance calculation between lncRNA-based clustering and other clusters identified in TCGA molecular, mRNA, miRNA and SCNA subtypes, respectively. We also investigated the association of lncRNA subclasses with distinct clinicopathological and genomic features of STAD. We found that C2 is significantly associated with MSI molecular subtype, MHL silencing, and mRNA C2, miRNA C2, methylation C2 subtypes. Cluster C3 is significantly associated with EBV-positive molecular subtype, CDKN2A silencing and mRNA C2, miRNA C2, methylation C1 subtypes; C4 is most significantly associated with CIN molecular subtype, p53 mutation and high SCNA, methylation C4 subtypes; C5 is significantly associated with GS molecular subtype, diffuse Lauren subtype, and mRNA C1, miRNA C4, methylation C1 subtypes. Interestingly, C5 defines the most aggressive tumors with the worst overall survival.

Conclusions: Our study represents the first comprehensive analysis of lncRNAs in STAD cancers, with integrative analysis revealing that the signatures of lncRNAs we characterize here appear to have prognostic significance. The additional association with the STAD molecular subtypes and genomic features supports new approaches to developing biomarkers and setting the stage for a new framework for future research in the role of lncRNAs in STAD.

Citation Format: Jian Chen, Jiun-Sheng Chen, Keping Xie, John R Stroehlein, Marta Davila, Xiaoping Su. Comprehensive analysis of long non-coding RNAs in human stomach adenocarcinoma molecular subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5405. doi:10.1158/1538-7445.AM2017-5405