Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma
As part of the Cancer Genome Atlas project, this study aimed to provide a comprehensive genomic characterization of Pheochromocytomas (PCC) and Paragangliomas (PGL) (n=173).
Molecular profiling was undertaken using 6 different tools: whole-exome sequencing (for mutations), SNP array (copy number variations), mRNA sequencing (gene expression, aberrant fusions), microRNA sequencing, DNA methylation and reverse-phase protein arrays.
Overall, these rare endocrine tumors have a low incidence of genomic alterations. In addition to the 2 subgroups already described in previous transcription studies - "pseudohypoxia" (including alterations in genes involved in regulation of hypoxia transcription factors VHL, EPAS, SDH, FH, MDH2, and IDH1) and "kinase signaling" (RET, HRAS, NF1), the group describes 2 additional transcriptional groups:
The "Wnt-altered" cluster of tumors is characterized by WNT pathway activation; novel MAML3 fusion gene and CSDE1 somatic mutation correlate with poor clinical outcome. This group of tumors expressed the highest levels of chromogranin A (CHGA, a clinical marker of neuroendocrine tumors that correlates with metastatic disease).
The forth cluster of "cortical admixture" tumors: despite higher content of normal tissue/leukocyte infiltration these had specific genetic alterations, such as MAX mutations, suggesting that they are a separate entity.
27% of the tumors were associated with a known germline mutation and exome sequencing did not reveal any novel germline mutations.
PCC/PGL comprise 4 different subgroups with specific genetic drivers. Amongst the many genetic drivers identified, specific mutations - both germline and somatic - were mutually exclusive.
Implications for clinical practice are the confirmation/identification of molecular markers of aggressive disease (SDHB, mutations ATRX and MAML3 fusions) and a rationale to explore targeted therapies (such as HIF in "pseudohypoxia" tumors and WNT proteins in "WNT signalling" tumors.

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