Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis.
Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in <i>ERBB2</i> amplifications and <i>TP53</i> mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and <i>PD-1</i>/<i>PD-L2</i> expression, or epigenetic mutations (<i>IDH1/2, BAP1</i>) and <i>FGFR</i>/<i>PRKA</i>-related gene rearrangements.
More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA.
Recent whole-exome and targeted sequencing not only confirmed frequent mutations in known CCA-related genes including TP53 (44%), KRAS (16.7%) and SMAD4 (16.7%), but also revealed mutations in novel CCA-related genes associated with chromatin remodeling [BAP1 (2.8%), ARID1A (17.6%), MLL3 (13%) and IDH1/2 (2.8%)], WNT signaling [RNF43 (9.3%) and PEG3 (5.6%)] and KRAS/G protein signaling [GNAS (9.3%) and ROBO2 (9.3%)].