Phaeochromocytomas (PC) and paragangliomas (PG) are neural crest cancers with high heritability. Recent advances in molecular profiling, including multi-omics and single cell genomics has identified up to seven distinct molecular subtypes. These subtypes are defined by mutations involving hypoxia-inducible factors (HIFs), Krebs cycle, kinase and WNT signalling, but are also defined by chromaffin differentiation states. PCPG have a dominant proangiogenic microenvironment linked to HIF pathway activity and are generally considered "immune cold" tumours with a high number of macrophages. PCPG subtypes can indicate increased metastatic risk but secondary mutations in telomere maintenance genes TERT or ATRX are required to drive the metastatic phenotype. Molecular profiling can identify molecular therapeutic (e.g. RET and EPAS1) and radiopharmaceutical targets while also helping to support variant pathogenicity and familial risk. Molecular profiling and subtyping of PCPG therefore confers the possibility of nuanced prognostication and individual treatment stratification but this still requires large-scale prospective validation.
Keywords: gene-expression profiling; genotype; next-generation sequencing; paraganglioma; phaeochromocytoma; subtypes.
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