Serum RARRES2 Is a Prognostic Marker in Patients With Adrenocortical Carcinoma

J Clin Endocrinol Metab. 2016 Sep;101(9):3345-52. doi: 10.1210/jc.2016-1781. Epub 2016 Jun 23.


Context: Retinoic acid receptor responder protein 2 (RARRES2) is a small secreted protein involved in multiple cancers, including adrenocortical carcinoma (ACC). However, discordant tumor and serum RARRES2 levels have been reported in various cancers. The etiology of this discordance is unknown and has not been studied in pair-matched tumor and serum samples.

Objective: To determine tissue and serum RARRES2 levels in patients with adrenocortical neoplasm and to elucidate the prognostic implications of RARRES2 levels.

Design, settings, and patients: Tissue and serum RARRES2 levels were analyzed. A pair-matched analysis was performed to examine tissue and serum RARRES2 from 51 patients with benign adrenocortical tumors and 18 patients with ACC. Overall survival was analyzed based on RARRES2 expression. A mouse xenograft model was used to determine the source of serum RARRES2.

Results: Patients with ACC had decreased tumor RARRES2 gene expression (P < .0001) and increased serum RARRES2 levels (P < .005) as compared with patients with benign adrenocortical tumors. Higher serum RARRES2 levels were associated with improved overall survival (P = .0227). A mouse xenograft model demonstrated that higher tissue RARRES2 expression was associated with higher RARRES2 secretion in the serum and that there was an intrinsic mechanism in maintaining serum RARRES2 homeostasis.

Conclusions: Serum and tissue RARRES2 expression levels are paradoxical in patients with ACC. The elevated RARRES2 in patient serum is unlikely to be secreted from tumor cells. Serum RARRES2 may be used as a novel prognostic marker for ACC.

Publication types

  • Comparative Study

MeSH terms

  • Adrenal Cortex Neoplasms / blood*
  • Adrenal Cortex Neoplasms / genetics
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Carcinoma / blood*
  • Adrenocortical Carcinoma / genetics
  • Adrenocortical Carcinoma / secondary
  • Adult
  • Aged
  • Animals
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / genetics
  • Blotting, Western
  • Case-Control Studies
  • Chemokines / blood*
  • Chemokines / genetics
  • Female
  • Follow-Up Studies
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Recurrence, Local / blood*
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tumor Cells, Cultured


  • Biomarkers, Tumor
  • Chemokines
  • Intercellular Signaling Peptides and Proteins
  • RARRES2 protein, human
  • RNA, Messenger