Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Genomic landscape of Phaeochromocytomas and Paragangliomas (#84)

Richard Tothill 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

Phaeochromocytomas and paragangliomas (PPGL) are remarkable for their high heritability and genetic heterogeneity. Between 30-40% of PPGL arise in the context of familial disease relating to constitutional mutations in up to 16 genes. A further 30% of sporadic cases can be explained by somatic mutations in these genes. Gene-expression profiling of PPGL has identified two major subtypes that correspond to the biochemical excretory profile and the gene drivers. The so-called “pseudo-hypoxia” subtype is noradrenergic and driven by dysregulation of HIF signalling either through mutations affecting Kreb-cycle pathway members (SDHA-D, SDHAF2, FH and MDH2) or mutations in VHL and HIF2A. The second major subtype consists of well-differentiated tumours with an adrenergic profile and mutations affecting kinase signalling (NF1, RET, HRAS, BRAF), apoptosis (KIF1B), mTOR signalling (TMEM127) and MYC (MAX). The somatic mutation burden in PPGL is low (~0.3/Mb) and surprisingly few recurrently mutated genes have been identified as co-operative drivers. Some somatically mutated cancer genes are associated with epigenetic modulation, genome maintenance and kinase signalling. Most PPGL genomes are relatively stable but recurrent somatic copy-number alterations (SCNAs) are a prominent feature. Regions of genomic loss encompass PPGL tumour suppressor genes as the required “second hit” equating to complete loss of gene function but other SCNAs occur ostensibly as independent co-operative events. Multi-region sampling and DNA sequencing of PPGL tumours furthermore suggests that SCNAs are the early and required events for tumourigenesis, while most subtle mutations occur as later events. Global DNA hypermethylation is apparent in PPGL driven by disruption of the Kreb cycle pathway, while microRNA expression patterns correspond to subtypes and gene drivers. The genomic landscape of PPGL is now coming into view. Challenges that lie ahead relate to identifying new familial PPGL genes, understanding gene penetrance within families, determining what drives malignant progression and identifying new therapeutic targets.