Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

The genomic landscape of phaeochromocytoma (#158)

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

Phaeochromocytomas (PC) and paragangliomas (PGL) arise from chromaffin cells of the adrenal medulla or the exta-adrenal sympathetic or parasympathetic ganglia. Most of these tumours secrete excess catecholamines that can cause debilitating hypertensive symptoms. Although the majority of PC/PGL are benign, 10-15% of cases develop metastatic disease and have a poor outcome. The disease is one of the most heritable forms of human neoplasia and up to one third of PC/PGL patients carry an autosomal dominant mutation in one of thirteen known genes. These genes have been broadly partitioned into two groups based on commonly altered pathways and distinct gene-expression profiles of the tumours. The so-called pseudo-hypoxia group includes mutations in HIF2a (EPAS1), HIF regulatory genes (e.g. VHL, PHD2) and Kreb cycle pathway members (SDHA-D, SDHF2, FH). The second group includes genes associated with receptor tyrosine kinase (RET), MAP kinase (NF1), mTOR (TMEM127) or MYC (MAX) regulation. Many of these genes are also somatically mutated in sporadic cases although one third of PC/PGL cases have no known driver. Furthermore, little is known of genes that can co-operate with the known oncogenic drivers to initiate tumorigenesis and dictate the tumour’s clinical behavior.  To explore the genomic landscape of PC/PGL we applied exome-sequencing, RNA-sequencing and high density SNP array analysis to 36 PC and 3 PGL tumours. Despite the tumours having a very low mutation rate we could identify pathogenic mutations in genes associated with DNA repair, genome maintenance, epigenetic modification and cytoskeletal remodeling. We revisited the gene-expression subtyping of PC/PGL by integrating published data with our RNA-seq data enabling identification of 6 subtypes. Strikingly, tumours belonging to one gene-expression subtype lacked mutations in known PC/PGL driver genes and had uncharacteristic copy-number profiles compared to other tumours.  This study provides new insight into the molecular diversity and genetic origins of PC/PGL tumours.