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IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma
Advanced Science ( IF 15.1 ) Pub Date : 2021-07-11 , DOI: 10.1002/advs.202101230
Xiao Xiang 1 , Ziyang Liu 2, 3 , Chong Zhang 2, 3 , Zhao Li 1 , Jie Gao 1 , Changkun Zhang 1 , Qi Cao 4 , Jinghui Cheng 4 , Hengkang Liu 4 , Dingbao Chen 1 , Qian Cheng 1 , Ning Zhang 4 , Ruidong Xue 4 , Fan Bai 2, 3 , Jiye Zhu 1
Affiliation  

Intrahepatic cholangiocarcinoma (ICC) is highly heterogeneous. Here, the authors perform exome sequencing and bulk RNA sequencing on 73 tumor regions from 14 ICC patients to portray the multi-faceted intratumor heterogeneity (ITH) landscape of ICC. The authors show that ITH is highly concordant across genomic, transcriptomic, and immune levels. Comparison of these data to 8 published datasets reveals significantly higher degrees of ITH in ICC than hepatocellular carcinoma. Remarkably, the authors find that high-ITH tumors highly overlap with the IDH (isocitrate dehydrogenase)-mutant subgroup (IDH-SG), comprising of IDH-mutated tumors and IDH-like tumors, that is, those IDH-wildtype tumors that exhibit similar molecular profiles to the IDH-mutated ones. Furthermore, IDH-SG exhibits less T cell infiltration and lower T cell cytotoxicity, indicating a colder tumor microenvironment (TME). The higher ITH and colder TME of IDH-SG are successfully validated by single-cell RNA sequencing on 17 503 cells from 4 patients. Collectively, the study shows that IDH mutant subgroup status, rather than IDH mutation alone, is associated with ITH and the TME of ICC tumors. The results highlight that IDH-like patients may also benefit from IDH targeted therapies and provide important implications for the diagnosis and treatment of ICC.

中文翻译:

IDH突变亚组状态与肝内胆管癌的肿瘤内异质性和肿瘤微环境相关

肝内胆管癌 (ICC) 具有高度异质性。在这里,作者对 14 名 ICC 患者的 73 个肿瘤区域进行外显子组测序和批量 RNA 测序,以描绘 ICC 的多方面肿瘤内异质性 (ITH) 格局。作者表明,ITH 在基因组、转录组和免疫水平上高度一致。将这些数据与 8 个已发表的数据集进行比较,发现 ICC 中 ITH 的程度显着高于肝细胞癌。值得注意的是,作者发现高 ITH 肿瘤与IDH(异柠檬酸脱氢酶)突变亚组(IDH -SG)高度重叠,包括IDH突变肿瘤和IDH样肿瘤,即那些IDH表现出与IDH突变的相似分子谱的野生型肿瘤。此外,IDH -SG 表现出较少的 T 细胞浸润和较低的 T 细胞细胞毒性,表明肿瘤微环境 (TME) 较冷。IDH -SG较高的 ITH 和较冷的 TME通过对 4 名患者的 17 503 个细胞进行单细胞 RNA 测序成功验证。总的来说,该研究表明IDH突变亚组状态,而不是单独的IDH突变,与 ITH 和 ICC 肿瘤的 TME 相关。结果强调,IDH样患者也可能受益于IDH靶向治疗,并为 ICC 的诊断和治疗提供重要意义。
更新日期:2021-09-09
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