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.