RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4
RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4
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DOI：
10.1016/j.molonc.2016.05.004
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发表时间：
2016-10-01
影响因子：
6.6
通讯作者：
Myers, Richard M.
中科院分区：
文献类型：
--
作者：
Kirby, Marie K.;Ramaker, Ryne C.;Myers, Richard M.
背景：胰腺腺癌患者由于诊断较晚，生存率较低，即使手术切除后也有较高的复发率。了解与胰腺腺癌肿瘤生存差异相关的分子特征是很重要的，这可能会为患者护理提供信息。结果：对51例手术切除患者的肿瘤组织进行了RNA测序，其表达与诊断后的总生存时间相关。我们的分析发现，在我们的胰腺患者队列中，323个转录本的表达与生存时间相关。这一基因组特征在来自国际癌症基因组联盟的另外68名患者的独立RNA-seq数据集中得到了验证。我们证明这种转录谱在很大程度上独立于细胞分裂标记，并提出了一个基于323个转录本子集的19个转录本预测模型，该模型可以区分训练和验证患者队列中不同生存时间的患者。我们提供的证据表明，生存相关转录本的一个子集与体外对吉西他滨治疗的耐药性有关，并揭示了一种生存相关转录本的表达减少，血管生成素样4，损害了吉西他滨耐药胰腺癌细胞系的生长。结论：胰腺腺癌肿瘤的基因表达模式可以区分手术切除后不同生存结局的患者，生存差异可能与原发患者肿瘤固有的吉西他滨敏感性有关。因此，这些转录差异可能通过区分哪些患者将受益于非吉西他滨治疗而影响患者护理。(C) 2016年欧洲生化学会联合会。Elsevier B.V.版权所有。
Background: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care.Results: RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line.Conclusions: Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy. (C) 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.