Intratumoral
IDH1
mutation status in intrahepatic cholangiocarcinoma is homogeneous
Sharon Weidmann, Silvana Ebner, Aayushi Srivastava, Armin Wiegering, Stefan Zeuzem, Peter J. Wild, Maximilian N. Kinzler, Melanie C. Winter, Dirk Walter 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.