Open AccessIDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma
Author(s) -
Xiang Xiao,
Liu Ziyang,
Zhang Chong,
Li Zhao,
Gao Jie,
Zhang Changkun,
Cao Qi,
Cheng Jinghui,
Liu Hengkang,
Chen Dingbao,
Cheng Qian,
Zhang Ning,
Xue Ruidong,
Bai Fan,
Zhu Jiye
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202101230
Subject(s) - isocitrate dehydrogenase , idh1 , intrahepatic cholangiocarcinoma , biology , transcriptome , cancer research , tumor microenvironment , exome sequencing , hepatocellular carcinoma , mutant , mutation , microbiology and biotechnology , gene , medicine , tumor cells , pathology , genetics , gene expression , biochemistry , enzyme
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.