Targeted genomic analysis of 364 adrenocortical carcinomas

Author:

Pozdeyev Nikita12,Fishbein Lauren12,Gay Laurie M3,Sokol Ethan S3,Hartmaier Ryan3,Ross Jeffrey S34,Darabi Sourat5,Demeure Michael J56,Kar Adwitiya1,Foust Lindsey J1,Koc Katrina1,Bowles Daniel W7,Leong Stephen7,Wierman Margaret E18,Kiseljak-Vassiliades Katja18

Affiliation:

1. 1Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus Aurora, Aurora, Colorado, USA

2. 2Division of Biomedical Informatics & Personalized Medicine, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus Aurora, Aurora, Colorado, USA

3. 3Foundation Medicine Inc., Cambridge, Massachusetts, USA

4. 4Departments of Pathology and Urology, Upstate Medical University, Syracuse, New York, USA

5. 5Hoag Family Center Institute, Newport Beach, California, USA

6. 6Translational Genomics Research Institute, Phoenix, Arizona, USA

7. 7Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus, Aurora, Colorado, USA

8. 8Research Service Veterans Affairs Medical Center, 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.

Publisher

Bioscientifica

Subject

Cancer Research,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism

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