RT Journal Article
SR Electronic
T1 Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 499
OP 511
DO 10.1136/gutjnl-2017-314353
VO 68
IS 3
A1 Arnes, Luis
A1 Liu, Zhaoqi
A1 Wang, Jiguang
A1 Maurer, Carlo
A1 Sagalovskiy, Irina
A1 Sanchez-Martin, Marta
A1 Bommakanti, Nikhil
A1 Garofalo, Diana C
A1 Balderes, Dina A
A1 Sussel, Lori
A1 Olive, Kenneth P
A1 Rabadan, Raul
YR 2019
UL http://gut.bmj.com/content/68/3/499.abstract
AB Objective Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome.Design We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA.Results We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673 and FAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines.Conclusions Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.