Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. As microRNAs (miRNAs) are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of miRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified miRNA signatures specific to, as well as common among, the genetic groups of PCCs/PGLs. miRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD-, and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using quantitative real-time PCR. Upregulation of miR-210 in VHL-and SDHB-related PCCs/PGLs was verified, while miR-137 and miR-382 were confirmed as generally upregulated in PCCs/PGLs (except in MAX-related tumors). Also, we confirmed overexpression of miR-133b as VHL-specific miRNAs, miR-488 and miR-885-5p as RET-specific miRNAs, and miR-183 and miR-96 as SDHB-specific miRNAs. To determine the potential roles miRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment Finally, global proteomic analysis in SDHB and MAX tumors allowed us to determine that miRNA regulation occurs primarily through mRNA degradation in PCCs/PGLs, which partially confirmed our miRNA-mRNA integration results.

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

“…Recently, de Cubas et al leveraged miRNA expression profiles to demonstrate that miR-137 and miR-382 were globally upregulated in all paragangliomas with the exception of MAX-related tumors, whereas miR-96, miR-183, and miR-210 were specifically upregulated in SDHB-related tumors. 30 While the exact mechanism by which miRNA aberrations contribute to paraganglioma formation in genetically predisposed individuals remains unclear, initial mRNA profiling data suggest that miRNA-mediated mRNA degradation results in a reduction in neuronal and neuroendocrine-associated development pathways. 30 Future studies in this area may leverage advances in RNA sequencing technologies to decipher the exact role of miRNA and mRNA in familial and sporadic paraganglioma tumorigenesis.…”

“…30 While the exact mechanism by which miRNA aberrations contribute to paraganglioma formation in genetically predisposed individuals remains unclear, initial mRNA profiling data suggest that miRNA-mediated mRNA degradation results in a reduction in neuronal and neuroendocrine-associated development pathways. 30 Future studies in this area may leverage advances in RNA sequencing technologies to decipher the exact role of miRNA and mRNA in familial and sporadic paraganglioma tumorigenesis.…”

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

“…Extensive clinical and genetic characterization over the last 25 years has greatly improved our knowledge about the genetic basis underlying PPGLs. Fortunately, application of high-throughput technologies to study PPGL has enhanced our understanding of tumor biology and has already led to novel therapeutic strategies, which may soon be applied in routine clinical practice (3)(4)(5)(6)(7). However, lack of reliable markers for metastatic disease and/or their limited predictive value continue to complicate the clinical management of patients with PPGL.…”

“…Previous cytogenetic, transcriptomic, and miRNA expression performed in PPGL have shed light on some of the molecular events underlying these tumors (3,4). Notwithstanding, the epigenetic landscape in PPGL has just only recently been explored (2,8).…”

Genetic Alterations in Pheochromocytoma and Paraganglioma

“…Sporadic tumors are represented in both clusters instead of forming clusters of their own, indicating that similar molecular mechanisms are involved. A recent study showed that expression profiling of microRNAs (which are small non-coding RNA molecules with important roles in modulating gene expression 144 ), also successfully classifies pheochromocytomas and paragangliomas into one VHL/SDHx cluster and one RET/NF1/TMEM127/MAX cluster 145 .…”