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Backman S, Axling F, Zhang L, Botling J, Juhlin CC, Barazeghi E, Skogseid B, Klimácek B, Annebäck M, Zedenius J, Norlén O, Stålberg P, Crona J, Åkerström T
Endocr. Pathol. 37 (1) - [2026-06-10; online 2026-06-10]
The mechanisms underlying how adrenocortical carcinoma (ACC) progresses into a metastatic and lethal disease remain poorly understood. To address this, we performed comprehensive genomic analyses to delineate the evolutionary trajectory of advanced ACC. Fresh frozen tumour samples (n = 29) were obtained from nine patients, all of whom had matched primary and relapse specimens, including recurrent (n = 4) and metastatic (n = 11) lesions. In four patients, multiple primary and metastatic samples were available, enabling detailed evolutionary comparisons. All tumours underwent whole-genome sequencing, RNA sequencing, and DNA methylation profiling. Our analyses revealed that seven of nine patients exhibited global loss of heterozygosity (LOH) often followed by whole-genome doubling, resulting in copy-neutral LOH. SNP-based analyses indicated that these alterations occurred as a single catastrophic event that was conserved across all matched samples within each patient, suggesting that this event constitutes a truncal feature of the evolutionary tree. These results support a model in which chromosomal aneuploidy is important in ACC tumourigenesis, potentially distinguishing carcinomas from benign adrenal adenomas. This may explain the rarity of adenoma-to-carcinoma transformation and suggest a diagnostic and therapeutic relevance of chromosomal instability in ACC.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 42265438
DOI 10.1007/s12022-026-09922-2
Crossref 10.1007/s12022-026-09922-2
pmc: PMC13249746
pii: 10.1007/s12022-026-09922-2