Figure 3. Molecular plasticity of hepatoblastoma across three differentiation states.

a Gene expression-based classification of hepatoblastoma. Unsupervised hierarchical clustering of 100 HB samples from 64 patients and 4 non-tumor liver samples revealed 4 molecular groups. Clinical and molecular annotations are depicted below the dendrogram, with p-values indicating their association with molecular groups. A heatmap shows the expression of key transcription factors (TF) and marker genes representative of each group, as well as molecular scores of hepatic differentiation, cell proliferation and immune infiltration. b Top: Proportion of transcriptomic groups and a selection of driver alteration frequencies at different steps of hepatoblastoma progression. Middle: Transcriptomic group switches identified in 24 patients with multiple sampling, including patients with pre/post-chemotherapy samples, synchronous samples at distinct locations in the primary tumor, and/or paired primary and relapse/metastasis. The number of patients with/without molecular switch is indicated for each type of multiple sampling, and the transcriptomic switch is represented by a color code on the arrows. Bottom: Examples of histological heterogeneity matching transcriptomic group switches. c Projection of hepatoblastomas and non-tumor liver samples over two independent methylation components. Hepatoblastomas are colored by their transcriptomic group, and samples from a same patient are linked with black lines. d Association of intra-sample histological heterogeneity with transcriptomic groups. e Association of intra-tumor histological heterogeneity with 11p15.5 locus alteration.