Genomic Catastrophe Defines the Evolutionary Trajectory of Adrenocortical Carcinoma

Figures

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  Fig. 1. Overview of the different genetic analyses and included specimens in the cohort

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  Fig. 2. (A) Oncoprint summarizing somatic mutations and copy number alterations identified in matched primary (P), metastatic (M), and recurrent (R) adrenocortical carcinoma (ACC) samples. Each column represents a tumour sample. TMB: Tumour mutation burden. SNV: Single nucleotide variants. LOH: Loss of heterozygosity in percent. MKi67, TERT: normalised expression using RNA sequencing. (B) Summary of ACC driver genes affecting the G1-S phase. P16 (CDKN2A), Cyclin E (CCNE1)

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  Fig. 3. Copy number alterations of the cohort. Heatmap showing copy number profiles for all analysed ACC samples, including primary (P), metastatic (M), and recurrent (R) tumours. Each column represents a chromosome (1–22), and each row corresponds to an individual sample

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  Fig. 4. (A) Heatmap showing SNP concordance between paired primary and relapse tumour samples across chromosomes. The colour gradient represents the percentage of SNP concordance between samples. Black boxes on the left mark chromosomes showing loss of heterozygosity (LOH). (B) Frequency of LOH across chromosomes in the cohort. Each bar represents the proportion of samples showing LOH for the corresponding chromosome

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  Fig. 5. Depiction of three patients with multiple samples in the cohort. The phylogenetic tree was created based on unique and shared mutations among samples using the raw phylogenetic trees in Supplementary Fig. 8. P: Primary, R: Recurrence, M: Metastasis, ACC: Adrenocortical carcinoma, WGD: Whole genome doubling, EDP: Etoposide, doxorubicin, cisplatin

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  Fig. 6. Proposed model of tumour evolution driven by loss of heterozygosity, whole-genome doubling, and subsequent subclonal diversification. A normal diploid (2 N) precursor cell acquires early clonal driver mutations¹ that promote tumour initiation. During mitosis, erroneous chromosome segregation leads to loss of heterozygosity (LOH), generating a haploid-like intermediate state (1 N). This unstable genome undergoes whole-genome doubling (WGD). As the tumour expands, additional subclonal mutations³ accumulate, contributing to intratumoral heterogeneity and the emergence of distinct subpopulations with variable fitness and treatment response. ¹ Early clonal driver mutations; ² Haploid-derived intermediate; ³ Later-arising subclonal mutations.