Genomic analyses identify molecular subtypes of pancreatic cancer
Genomic analyses identify molecular subtypes of pancreatic cancer
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DOI：
10.1038/nature16965
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发表时间：
2016-03-03
期刊：
影响因子：
64.8
通讯作者：
Grimmond, Sean M.
中科院分区：
文献类型：
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作者：
Bailey, Peter;Chang, David K.;Grimmond, Sean M.
对456例胰腺导管腺癌的综合基因组分析确定了32个复发突变的基因，这些基因聚集成10个通路：KRAS、TGF-β、WNT、NOTCH、ROBO/SLIT信号传导、G1/S转换、SWI-SNF、染色质修饰、DNA修复和RNA加工。表达分析定义了4种亚型：（1）鳞状;（2）胰腺祖细胞;（3）免疫原性;和（4）与组织病理学特征相关的异常分化内分泌外分泌（ADEX）。鳞状细胞肿瘤富含TP 53和KDM 6A突变、TP 63 Delta N转录网络的上调、胰腺内胚层细胞命运决定基因的超甲基化，并且具有不良预后。胰腺祖细胞肿瘤优先表达参与早期胰腺发育的基因（FOXA 2/3、PDX 1和MNX 1）。ADEX肿瘤显示调节KRAS激活、外分泌（NR 5A 2和RBPJL）和内分泌分化（NEUROD 1和NKX 2 -2）网络的基因上调。免疫原性肿瘤含有上调的免疫网络，包括参与获得性免疫抑制的途径。这些数据推断胰腺癌亚型的分子进化差异，并确定治疗发展的机会。
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63 Delta N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.