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Updated: Sep 25, 2025
An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues
Published on: April 5, 2018
Whole-genome and transcriptome analysis of advanced adrenocortical cancer highlights multiple alterations affecting
Jean-Michel Lavoie1, Veronika Csizmok2, Laura M Williamson2
1Department of Medical Oncology, BC Cancer, Surrey, British Columbia V3V 1Z2, Canada.
Abstract:
Adrenocortical cancer (ACC) is a rare cancer of the adrenal gland. Several driver mutations have been identified in both primary and metastatic ACCs, but the therapeutic options are still limited. We performed whole-genome and transcriptome sequencing on seven patients with metastatic ACC. Integrative analysis of mutations, RNA expression changes, mutation signature, and homologous recombination deficiency (HRD) analysis was performed. Mutations affecting CTNNB1 and TP53 and frequent loss of heterozygosity (LOH) events were observed in our cohort. Alterations affecting genes involved in cell cycle (RB1, CDKN2A, CDKN2B), DNA repair pathways (MUTYH, BRCA2, ATM, RAD52, MLH1, MSH6), and telomere maintenance (TERF2 and TERT) consisting of somatic and germline mutations, structural variants, and expression outliers were also observed. HRDetect, which aggregates six HRD-associated mutation signatures, identified a subset of cases as HRD. Genomic alterations affecting genes involved in epigenetic regulation were also identified, including structural variants (SWI/SNF genes and histone methyltransferases), and copy gains and concurrent high expression of KDM5A, which may contribute to epigenomic deregulation. Findings from this study highlight HRD and epigenomic pathways as potential therapeutic targets and suggest a subgroup of patients may benefit from a diverse array of molecularly targeted therapies in ACC, a rare disease in urgent need of therapeutic strategies.
Insights
This study reveals homologous recombination deficiency (HRD) and epigenomic alterations in metastatic adrenocortical cancer (ACC). These findings suggest new therapeutic targets for this rare cancer, offering hope for improved patient outcomes.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Adrenocortical cancer (ACC) is a rare endocrine malignancy with limited therapeutic options.
- Driver mutations are known in ACC, but a comprehensive understanding of genomic alterations in metastatic disease is needed.
Purpose of the Study:
- To investigate the genomic landscape of metastatic adrenocortical cancer (ACC) using whole-genome and transcriptome sequencing.
- To identify potential therapeutic targets by analyzing mutations, gene expression, and homologous recombination deficiency (HRD).
Main Methods:
- Whole-genome and transcriptome sequencing of seven metastatic ACC patients.
- Integrative analysis of mutations, RNA expression, mutation signatures, and HRD.
- Utilized HRDetect to identify HRD-associated mutation signatures.
Main Results:
- Identified mutations in CTNNB1 and TP53, frequent loss of heterozygosity (LOH), and alterations in cell cycle, DNA repair, and telomere maintenance genes.
- A subset of ACC cases showed homologous recombination deficiency (HRD).
- Genomic alterations in epigenetic regulation, including KDM5A overexpression, were observed.
Conclusions:
- Homologous recombination deficiency (HRD) and epigenomic pathways are potential therapeutic targets in ACC.
- Molecularly targeted therapies may benefit a subgroup of ACC patients.
- This research provides insights into the molecular basis of ACC, addressing an urgent need for novel treatment strategies.
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