Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma.
Luis Arnes, Zhaoqi Liu, Jiguang Wang, Carlo Maurer, Irina Sagalovskiy, Marta Sanchez-Martin, Nikhil Bommakanti, Diana C Garofalo, Dina A Balderes, Lori Sussel, Kenneth P Olive, Raul Rabadan
Author Information
Luis Arnes: Department of Systems Biology, Columbia University Medical Center, New York City, New York, USA. ORCID
Zhaoqi Liu: Department of Systems Biology, Columbia University Medical Center, New York City, New York, USA.
Jiguang Wang: Department of Biomedical Informatics, Columbia University Medical Center, New York City, New York, USA.
Carlo Maurer: Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City, New York, USA.
Irina Sagalovskiy: Department of Systems Biology, Columbia University Medical Center, New York City, New York, USA.
Marta Sanchez-Martin: Institute for Cancer Genetics, Columbia University Medical Center, New York City, New York, USA.
Nikhil Bommakanti: Department of Systems Biology, Columbia University Medical Center, New York City, New York, USA.
Diana C Garofalo: Department of Genetics and Development, Columbia University Medical Center, New York City, New York, USA.
Dina A Balderes: Department of Genetics and Development, Columbia University Medical Center, New York City, New York, USA.
Lori Sussel: Department of Genetics and Development, Columbia University Medical Center, New York City, New York, USA.
Kenneth P Olive: Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City, New York, USA.
Raul Rabadan: Department of Systems Biology, Columbia University Medical Center, New York City, New York, USA.
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 ( and ) 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.
