Cancer Cell. 2017 Aug 14;32(2):185-203.e13. doi: 10.1016/j.ccell.2017.07.007.
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
我们对150份胰腺导管腺癌（PDAC）标本进行了综合基因组、转录组和蛋白质组分析，包括具有低肿瘤细胞特征的样本。深度全外显子测序揭示了KRAS、TP53、CDKN2A、SMAD4、RNF43、ARID1A、TGFβR2、GNAS、RREB1和PBRM1等基因的复发性体细胞突变。KRAS野生型肿瘤在其他致癌驱动基因中存在改变，包括GNAS、BRAF、CTNNB1和其他RAS通路基因。一部分肿瘤存在多个KRAS突变，其中一些显示出双等位基因突变的证据。蛋白质分析确定了一个预后良好的亚组，其上皮-间质转化程度低且MTOR通路得分高。还确定了非编码RNA与肿瘤特异性mRNA亚型之间的关联。我们的综合多平台分析揭示了PDAC复杂的分子格局，并为精准医学提供了路线图。
