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Genomic Catastrophe Defines the Evolutionary Trajectory of Adrenocortical Carcinoma

Samuel Backman1, Fredrik Axling1, Liang Zhang2

  • 1Department of Surgical Sciences, Uppsala University Hospital, 75185, Uppsala, Sweden.

Endocrine Pathology
|June 9, 2026
PubMed

Insights

Genomic analysis reveals a catastrophic chromosomal event, global loss of heterozygosity, drives adrenocortical carcinoma (ACC) evolution. This instability may explain ACC

Area of Science:

  • Genomics
  • Cancer Biology
  • Evolutionary Medicine

Background:

  • Adrenocortical carcinoma (ACC) progression to metastatic disease is poorly understood.
  • Mechanisms driving ACC lethality require elucidation.
  • Understanding ACC evolution is crucial for therapeutic development.

Purpose of the Study:

  • To delineate the evolutionary trajectory of advanced adrenocortical carcinoma (ACC).
  • To identify genomic alterations driving ACC progression.
  • To explore the role of chromosomal instability in ACC tumorigenesis.

Main Methods:

  • Comprehensive genomic analyses of 29 tumor samples from 9 patients with matched primary and relapse lesions.
  • Whole-genome sequencing, RNA sequencing, and DNA methylation profiling.
  • Single Nucleotide Polymorphism (SNP)-based analyses to track evolutionary events.

Main Results:

  • Seven of nine patients showed global loss of heterozygosity (LOH) followed by whole-genome doubling, creating copy-neutral LOH.
  • This catastrophic LOH event was conserved across all matched primary and metastatic samples within patients, indicating a truncal evolutionary feature.
  • Chromosomal aneuploidy appears critical in ACC tumorigenesis, potentially differentiating it from benign adrenal adenomas.

Conclusions:

  • A single, catastrophic chromosomal event (global LOH) is a key driver in adrenocortical carcinoma (ACC) evolution.
  • Chromosomal instability is implicated in ACC development and may explain the rarity of adenoma-to-carcinoma transformation.
  • Findings suggest diagnostic and therapeutic relevance of chromosomal instability in ACC management.
Keywords:
Adrenocortical carcinomaCopy number alterationsEndocrine cancerTumour evolutionWhole genome sequencing

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