Malignancy in Pheochromocytoma or Paraganglioma: Integrative Analysis of 176 Cases in TCGA

Methods of diagnosing malignant pheochromocytoma (PCC) or paraganglioma (PGL) are needed. However, there are no reliable histopathologic criteria to distinguish malignant PCC/PGLs. The recent genomic analysis of The Cancer Genome Atlas (TCGA) provides in-depth information enabling more accurate diagnosis of disease entities. Therefore, we investigated genomic expression differences and mutational differences of malignant PCC/PGLs with TCGA. As of December 2014, TCGA had acquired multigenomic analysis of 176 PCC/PGL samples. Clinical information, mutation status, and 20,531 gene messenger RNA (mRNA) expression dataset of normalized RNA-sequencing mRNA read counts were downloaded from TCGA, and integrated into a table. Of the 176 PCC/PGL samples in the dataset, 14 had metastasis and 162 exhibited no metastasis. mRNA expression and mutations were compared in these two groups. There were 76 males in the dataset of 176 TCGA samples. Mean age was 47.6 ± 15.2 years (19–83 years). There was no significant gender or race difference between metastatic and non-metastatic groups. mRNA expression of malignant PCC/PGLs was upregulated in five pathways of cell cycle (BUB1, BUB1B, CCNB2, CDC2, ESPL1), calcium signaling (CCNB2, CDC2, PRKCB1), regulation of actin cytoskeleton (DIAPH3, FGF18, IQGAP3), gap junction (CDC2, PRKCB1), and phosphatidylinositol (PRKCB1, TTK). Disease-free survival rates were significantly correlated with the presence or absence of mutations, such as RP11-798G7.5, HERC2, SETD2, TGDS, TRHDE, FKBP9, and BMS1. TCGA showed differences in mRNA expression and mutations between metastatic and non-metastatic PCC/PGLs. The improved recognition of genetic causes can help to achieve proper diagnosis and provide appropriate treatment of PCC/PGL.