Poster Presentation 32nd Lorne Cancer 2020

TERT and ATRX mutations are associated with metastasis in SDHB mutated phaeochromocytomas and paragangliomas (#327)

Andrew Pattison 1 , Shiva Balachander 1 , Trisha Dwight 2 , Lauren Fishbein 3 , Fernando Rossello 1 , Luciano Martelotto 1 , Magnus Zethoven 4 , Alison Trainer 4 , Thomas Giordano 5 , Hans Kumar Ghayee 6 , Isabelle Bourdeau 7 , Marianne Elston 8 , Joanne Ngeow Yuen Yie 9 , Diana E Benn 2 , Joakim Crona 10 , Tobias Akerstrom 10 , Peter Stålberg 10 , Sean Grimmond 1 , Oliver Hofmann 1 , Patricia Dahia 11 , Arthur Tischler 12 , Tobias Else 5 , Anthony Gill 13 , Rod Hicks 4 , Roderick Clifton-Bligh 2 , Karel Pacak 14 , Richard Tothill 1
  1. UNIVERSITY OF MELBOURNE, Melbourne, VIC, Australia
  2. Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia
  3. University of Colorado, Boulder, CO, USA
  4. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. University of Michigan, Ann Arbor, MI, USA
  6. University of Florida, Gainesville, FL, USA
  7. Centre hospitalier de l' Université de Montréal, Montréal, Canada
  8. University of Auckland, Auckland, New Zealand
  9. National Cancer Centre, Singapore
  10. Uppsala University, Uppsala, Sweden
  11. University of Texas Health Science Center, San Antonio, TX, USA
  12. Tufts Medical Centre, Boston, MA, USA
  13. Royal North Shore Hospital/University of Sydney, Sydney, NSW, Australia
  14. National Institute of Health, Bethesda, MD, USA

Phaeochromocytomas and paragangliomas (PPGL) are ultra-rare but highly heritable neuroendocrine tumours arising from sympathetic and parasympathetic tissues. Most PPGL secrete catecholamines (e.g. adrenaline, noradrenaline) causing paroxysmal symptoms such as hypertension, headache and tachycardia. Up to 20% of PPGL become metastatic with highest risk amongst patients carrying pathogenic SDHB mutations. However, even amongst this higher risk group, approximately two thirds don’t metastasise. With no recognised biomarkers of metastatic risk and no cure in the metastatic setting there is a clear need to better understand the molecular drivers of metastasis. We present here preliminary results of the international A5 SDHB Genomics Study, representing the most comprehensive analysis of SDHB-associated PPGL to date.

 

The A5 study cohort consists of 99 distinct tumour samples with matched blood from 84 patients. These samples have extensive clinical annotation and have been comprehensively analysed using whole genome sequencing (WGS), RNA-Sequencing (RNA-Seq) and histopathological review, with a subset analysed by single-nuclei RNA-Seq (snRNA-seq) and single-nuclei ATAC-Seq (snATAC-seq). TERT promoter mutations and a promoter-associated TERT structural rearrangement as well as gene disruptive ATRX mutations were most commonly associated with metastasis. TERT promoter mutations and rearrangements corresponded with TERT mRNA overexpression in tumours and open chromatin around the TERT promoter as indicated by snATAC-seq. Additionally, in one primary-metastasis pair a TERT promoter mutation was detected at subclonal levels in the primary tumour that subsequently became the dominant metastatic clone. Subclonal tumour-specific TERT expression was confirmed in this sample using snRNA-seq. TERT is the catalytic subunit of telomerase and it is likely that the activation of this gene allows for uncontrolled proliferation by maintaining telomere length in dividing cells. Similarly, mutations in ATRX were associated with alternative lengthening of telomeres suggesting contribution to tumour immortalisation through analogous mechanisms. While analysis is continuing, these preliminary findings confirm TERT and ATRX mutations as being associated with metastatic PPGL and that testing for TERT and ATRX mutations may predict the likelihood of disease progression.