RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights

J Clin Endocrinol Metab. 2020 Dec 1;105(12):dgaa616. doi: 10.1210/clinem/dgaa616.

Abstract

Context: Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure.

Objective: To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms.

Design: Cross-sectional study.

Setting: University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT).

Patients: We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs).

Intervention: Ribonucleic acid (RNA) sequencing.

Main outcome measures: Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing.

Results: Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation.

Conclusions: MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Keywords: Cushing syndrome; adrenocortical adenoma; gene fusions; long non-coding RNA; mild autonomous cortisol excess; transcriptome.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / epidemiology
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Adenoma / epidemiology
  • Adrenocortical Adenoma / genetics*
  • Adrenocortical Adenoma / pathology
  • Aged
  • Cross-Sectional Studies
  • Cushing Syndrome / epidemiology
  • Cushing Syndrome / genetics
  • Cushing Syndrome / pathology
  • DNA Mutational Analysis / methods
  • Europe / epidemiology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Oncogene Proteins, Fusion / analysis
  • Oncogene Proteins, Fusion / genetics
  • RNA, Long Noncoding / genetics
  • RNA-Seq
  • Retrospective Studies
  • Sequence Analysis, RNA
  • Transcriptome

Substances

  • Oncogene Proteins, Fusion
  • RNA, Long Noncoding