Intratumoral IDH1 mutation status in intrahepatic cholangiocarcinoma is homogeneous

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INTRODUCTION: IDH1 mutations occur in approximately 10%-20% of intrahepatic cholangiocarcinoma (iCCA) and constitute an established target for molecularly guided therapy. As routine molecular diagnostics are commonly based on a single tumour sample, intratumoral heterogeneity could affect the reliable detection of actionable mutations. This study assessed the spatial heterogeneity of IDH1 mutations in iCCA. METHODS: Patients with histologically confirmed iCCA who underwent routine next-generation sequencing (NGS) and had multiple available formalin-fixed paraffin-embedded (FFPE) tumour samples were retrospectively analysed. Baseline IDH1 status was determined by NGS. All available tumour regions were subsequently tested using the Idylla™ IDH1-2 Mutation Assay. Blocks where the Idylla™ IDH1 mutational status was discordant with baseline status were validated by digital polymerase chain reaction (dPCR). RESULTS: Thirty-five patients with iCCA were included, yielding 117 FFPE samples from spatially distinct tumour regions. Baseline NGS identified IDH1 mutations in 22.8% (8/35) of patients. Idylla™ testing revealed discordant results in 5 of 117 samples (4.2%). Validation by dPCR demonstrated that these discordances were attributable to technical limitations or assay-related errors rather than true biological heterogeneity. Following validation, all IDH1-mutated tumours showed concordant mutation status across all analysed tumour regions. CONCLUSIONS: IDH1 mutations appear to be spatially homogeneous in iCCA, supporting their role as an early clonal event. These findings indicate that single-sample molecular testing is sufficient for reliable determination of IDH1 status and patient selection for IDH1-targeted therapies.

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