Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma.
Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma.
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DOI：
10.1002/hep.29764
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Andersen JB
中科院分区：
文献类型：
--
作者：
Nepal C;O'Rourke CJ;Oliveira DVNP;Taranta A;Shema S;Gautam P;Calderaro J;Barbour A;Raggi C;Wennerberg K;Wang XW;Lautem A;Roberts LR;Andersen JB
肝内胆管癌（iCCA）仍然是一种高度异质性的恶性肿瘤，迄今为止尚未对患者进行有效的分层。这种异质性在多大程度上受个体驱动突变的影响仍有待评估。在这里，我们分析了 496 名患者的基因组（全外显子组测序、靶向外显子组测序）和表观基因组数据，并使用三个最常突变的基因对患者进行分层（IDH、KRAS、TP53，“未确定”）。使用这种分子解剖方法，每个亚组都被确定为具有独特的突变特征偏好、共突变谱和丰富的途径。在七个患者匹配的细胞系中进行高通量药物重新定位，选择反映每个患者组特有的遗传改变，在计算机模拟中证实了与丰富途径相关的亚组特异性脆弱性的预测。有趣的是，缺乏所有 3 个突变（“未确定”）的患者具有最广泛的结构改变，而 IDH 突变肿瘤则表现出最广泛的 DNA 甲基化失调，这与之前的发现一致。根据三个分类基因（IDH、KRAS、TP53）突变的发生对 iCCA 患者进行分层，揭示了影响药物重新定位方案中药理反应的独特致癌程序（突变、结构、表观突变）。这种基因组解剖方法强调了个体突变诱导广泛分子异质性的潜力，并可能促进这种令人沮丧的疾病的治疗反应的进展。
Intrahepatic cholangiocarcinoma (iCCA) remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients, and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, ‘undetermined’). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, co-mutation profiles and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all 3 mutations (‘undetermined’) harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings. Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) that influence pharmacologic response in drug repositioning protocols. This genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
65.1
作者：
Banales, Jesus M.;Cardinale, Vincenzo;Alvaro, Domenico
通讯作者：
Alvaro, Domenico
影响因子：
5
作者：
Andersen JB;Thorgeirsson SS
通讯作者：
Thorgeirsson SS
影响因子：
12.3
作者：
Feber A;Guilhamon P;Lechner M;Fenton T;Wilson GA;Thirlwell C;Morris TJ;Flanagan AM;Teschendorff AE;Kelly JD;Beck S
通讯作者：
Beck S
影响因子：
28.2
作者：
Pemovska, Tea;Kontro, Mika;Wennerberg, Krister
通讯作者：
Wennerberg, Krister