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.

中文翻译：

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与胰腺导管腺癌相关的隔室特异性长链非编码 RNA 的综合表征

目的胰腺导管腺癌 (PDA) 是一种高度转移性疾病，治疗选择有限。基因组和转录组分析已经确定了对患者分层和靶向治疗有影响的信号通路和癌症驱动基因。然而，这些分析是在大量样本中进行的，并侧重于编码基因，这些基因代表了基因组的一小部分。设计 我们开发了一个计算框架，用于从横截面 RNA-Seq 重建非编码转录组，整合体细胞拷贝数改变 (SCNA)、与 PDA 风险和临床结果相关的常见种系变异。我们在来自激光捕获显微解剖的人类胰腺肿瘤的成对上皮和基质 RNA-Seq 的独立队列中验证了结果，允许我们注释他们表达的隔间特异性。我们采用系统和实验生物学方法来研究与 PDA 中的遗传特征和临床结果相关的上皮长链非编码 RNA (lncRNA) 的功能。结果 我们生成了 PDA 相关 lncRNA 的目录。我们发现 lncRNA 定义了具有生物学和临床意义的分子亚型。我们使用 PDA 中的基因组和临床数据确定了具有 SCNA 和单核苷酸多态性的基因组区域中的 lncRNA，这些多态性与 PDA 的终生风险相关，并且与临床结果相关。两种上皮 lncRNA（LINC00673 和 FAM83H-AS1）的系统生物学和实验功能分析表明它们调节胰腺肿瘤样本和 PDA 细胞系的转录谱。