Two classes of intrahepatic cholangiocarcinoma defined by relative abundance of mutations and copy number alterations.

Intrahepatic cholangiocarcinoma (ICC) is a biliary tree-origin epithelial malignancy in liver with unfavorable clinical outcomes. Systematic genome analyses may advance our understanding of ICC pathogenesis also improving current diagnostic and therapeutic modalities. In this study, we analyzed 17 ICC tumor-vs-matched normal pairs using either whole-exome (n = 7), transcriptome sequencing (n = 7) or both platforms (n = 3). For somatic mutations, we identified recurrent mutations of previously reported genes such as KRAS, TP53, APC as well as epigenetic regulators and those of TGFβ signaling pathway. According to the abundance of somatic mutations and DNA copy number alterations (CNA), ten ICC exome cases were distinguished into two classes as those primarily driven by either somatic mutations (M class) or CNAs (C class). Compared to M class ICCs (92-147 somatic mutations; n = 5) with a relative deficit of CNAs, C class ICCs (54-84 mutations; n = 5) harbor recurrent focal CNAs including deletions involving CDKN2A, ROBO1, ROBO2, RUNX3, and SMAD4. We also show that transcriptome sequencing can be used for expression-based ICC categorization but the somatic mutation calling from the transcriptome can be heavily influenced by the gene expression level and potentially, by posttranscriptional modification such as nonsense mediated decay. Along with a substantial level of mutational heterogeneity of ICC genomes, our study reveals previously unrecognized two ICC classes defined by relative abundance of somatic mutations over CNAs or vice versa, which should be considered in the selection of genotyping platforms and sensitive screening of targets for ICC therapeutics.