Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

J Clin Pathol. 2014 Nov;67(11):968-73. doi: 10.1136/jclinpath-2014-202514. Epub 2014 Jul 30.

Abstract

Aims: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.

Methods: DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).

Results: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.

Conclusions: Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

Keywords: Cancer Genetics; Endocrine Pathology; Gene Amplification; Molecular Pathology; Oncology.

MeSH terms

  • Adrenal Cortex Neoplasms / drug therapy*
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / metabolism
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / drug therapy*
  • Adrenocortical Carcinoma / genetics*
  • Adrenocortical Carcinoma / metabolism
  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Biopsy
  • Drug Design
  • Female
  • Gene Expression Profiling / methods*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Patient Selection
  • Precision Medicine
  • Predictive Value of Tests
  • Retrospective Studies
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor