Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma

J Clin Endocrinol Metab. 2016 Mar;101(3):1034-43. doi: 10.1210/jc.2015-3889. Epub 2016 Jan 21.

Abstract

Context: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers.

Objective: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology.

Design: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential.

Results: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application.

Conclusions: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / classification*
  • Adrenal Gland Neoplasms / genetics*
  • Gene Expression
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Membrane Proteins / genetics
  • Mutation
  • Neurofibromin 1 / genetics
  • Paraganglioma / classification*
  • Paraganglioma / genetics*
  • Pheochromocytoma / classification*
  • Pheochromocytoma / genetics*
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • RNA / analysis
  • Succinate Dehydrogenase / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • Membrane Proteins
  • Neurofibromin 1
  • TMEM127 protein, human
  • RNA
  • Succinate Dehydrogenase
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • VHL protein, human