Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-Specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma.
Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-Specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma.
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激光捕获微解剖肿瘤的转录组学分析揭示了胰腺导管腺癌的癌症和基质特异性分子亚型。
DOI：
10.1158/1078-0432.ccr-20-1039
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发表时间：
2021-04-15
期刊：
影响因子：
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通讯作者：
Liss AS
中科院分区：
文献类型：
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作者：
Birnbaum DJ;Begg SKS;Finetti P;Vanderburg C;Kulkarni AS;Neyaz A;Hank T;Tai E;Deshpande V;Bertucci F;Birnbaum D;Lillemoe KD;Warshaw AL;Mino-Kenudson M;Fernandez-Del Castillo C;Ting DT;Liss AS
胰腺导管腺癌（PDAC）的致死性是多因素的;尽管研究已经确定了具有不同预后意义的肿瘤的转录和遗传子集，但对少数手术切除后持久缓解的患者相关特征的理解有限。在这项研究中，我们对PDAC样本进行了激光捕获显微切割（LCM），以确定其癌症和基质特异性分子亚型，并确定短期和长期生存的预后基因表达特征。对19例未经治疗的PDAC肿瘤的癌症和邻近基质进行LCM和RNA-seq分析。在一个大的独立验证集中测试基因表达特征的稳健性。一种RNA原位杂交（RNA-ISH）检测与无病生存期（DFS）相关的基因的探针池开发探针111 PDAC肿瘤样本。基因表达谱鉴定了四种癌细胞亚型（C1-C4）和三种癌旁基质亚型（S1-S3）。这些基质特异性亚型与DFS相关（p=5.55E-07），当与C1和C2配对时，S1与更好的预后相关。发现13个基因主要在癌细胞中表达，并在使用现有RNA-seq数据集的验证中与DFS相对应。使用针对这些预后基因中的六个的RNA-ISH探针对独立的患者队列进行的第二次验证表明与总生存期显著相关（中位数17对25个月; p<0.02）。我们的研究结果确定了PDAC的上皮和基质成分的特异性特征，这增加了PDAC分子亚型的性质的清晰度，并可能有助于预测生存。
Pancreatic ductal adenocarcinoma (PDAC) lethality is multifactorial; although studies have identified transcriptional and genetic subsets of tumors with different prognostic significance, there is limited understanding of features associated with the minority of patients who have durable remission after surgical resection. In this study, we performed laser capture microdissection (LCM) of PDAC samples to define their cancer- and stroma-specific molecular subtypes and identify a prognostic gene expression signature for short-term and long-term survival. LCM and RNA-seq analysis of cancer and adjacent stroma of 19 treatment-naïve PDAC tumors were performed. Gene expression signatures were tested for their robustness in a large independent validation set. An RNA in situ hybridization (RNA-ISH) assay with pooled probes for genes associated with disease-free survival (DFS) was developed to probe 111 PDAC tumor samples. Gene expression profiling identified four subtypes of cancer cells (C1–C4) and three subtypes of cancer-adjacent stroma (S1–S3). These stroma-specific subtypes were associated with DFS (p=5.55E-07), with S1 associated with better prognoses when paired with C1 and C2. Thirteen genes were found to be predominantly expressed in cancer cells and corresponded with DFS in a validation using existing RNA-seq datasets. A second validation on an independent cohort of patients using RNA-ISH probes to six of these prognostic genes demonstrated significant association with overall survival (median 17 versus 25 months; p<0.02). Our results identified specific signatures from the epithelial and the stroma components of PDAC, which add clarity to the nature of PDAC molecular subtypes and may help predict survival.