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Updated: Oct 23, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeted genomic analysis of 364 adrenocortical carcinomas
Nikita Pozdeyev1,2, Lauren Fishbein1,2, Laurie M Gay3
1Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus Aurora, Aurora, Colorado, USA.
Abstract:
Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.
Insights
Genomic profiling of adrenocortical carcinoma (ACC) revealed actionable alterations in over half of patients. DNA mismatch repair gene alterations suggest immunotherapy may benefit a significant subset of ACC patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Adrenocortical carcinoma (ACC) is an orphan malignancy with poor survival rates.
- Identifying targetable genomic alterations is crucial for improving patient outcomes.
- Recent advances in understanding ACC molecular pathways necessitate comprehensive genomic characterization.
Purpose of the Study:
- To characterize the genomic profile of a large adrenocortical carcinoma cohort.
- To identify actionable genomic alterations for potential targeted therapies.
- To explore novel gene alterations associated with ACC.
Main Methods:
- Whole-exome sequencing or targeted sequencing of 364 individual patient ACC tumors.
- Analysis of common alteration pathways including epigenetic modification, telomere lengthening, SWI/SNF complex, tumor suppressor genes, and WNT signaling.
- Identification of mutations in DNA mismatch repair (MMR) pathway genes.
Main Results:
- Over half (58.5%) of ACC tumors harbored at least one potentially actionable genomic alteration across 46 genes.
- Frequent alterations were observed in epigenetic pathways (38%), telomere lengthening (21%), SWI/SNF complex (21%), tumor suppressor genes (51%), and WNT signaling (51%).
- A significant subset (13.7%) of ACC tumors showed alterations in DNA mismatch repair (MMR) genes, often with high mutation burdens and MMR mutation signatures.
Conclusions:
- Targeted sequencing is valuable for identifying actionable genomic alterations in adrenocortical carcinoma.
- The high prevalence of actionable alterations supports personalized treatment strategies for ACC.
- The notable incidence of MMR gene alterations indicates immunotherapy as a promising therapeutic option for a substantial portion of ACC patients.
