Oral Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

A Bayesian approach to determining penetrance of pathogenic variants in genes for hereditary pheochromocytoma/paraganglioma syndromes (#21)

Diana (Dindy) Benn 1 2 3 , Ying Zhu 2 3 4 , Edward Kim 2 3 , Mathilda Wilding 4 , Ashley Crook 4 , Anne Louise Richardson 2 , Catherine Luxford 2 , Richard Tothill 5 6 , Emma L Duncan 7 8 9 , Trish Dwight 2 3 , Arran Schlosberg 3 , Katherine Tucker 10 , Rod J Hicks 5 6 , Alison Trainer 5 6 , John Burgess 11 , Rachel Susman 12 , Lyndal Tacon 1 2 3 , Bruce G Robinson 1 2 3 , Anthony J Gill 13 14 , Michael Field 4 , Roderick Clifton-Bligh 1 2 3
  1. Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW, Australia
  2. Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia
  3. University of Sydney, Sydney, NSW, Australia
  4. Northern Sydney Local Health District Familial Cancer Service, Royal North Shore Hospital, St Leonards, NSW, Australia
  5. The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  7. Queensland University of Technology, Brisbane, Queensland, Australia
  8. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  9. Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  10. Department of Clinical Genetics, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia
  11. University of Tasmania, Hobart, Tasmania, Australia
  12. Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  13. RNSH, Glebe, NSW, Australia
  14. Cancer Diagnosis and Pathology Group , Kolling Institute of Medical Research, Sydney, NSW, Australia

Up until recently, determining penetrance of pathogenic variants required large observational cohort studies. The availability of large population cohort data in the Exome Aggregate Consortium (ExAC) now makes it possible to use a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from our genetic testing for medullary thyroid cancer (MTC) and pheochromocytoma/paraganglioma (PC/PGL) susceptibility genes. Frequency of each pathogenic variant found in RET, SDH subunit genes A-D and VHL in our cases was compared with its frequency in ExAC.

Genetic testing was performed in 437 Australian subjects presenting with MTC and 575 subjects presenting with PC/PGL. We identified pathogenic RET variants in 58 subjects (13.3%) presenting with MTC, and pathogenic RET, SDHx, or VHL variants in 162 subjects (28.3%) presenting with pheochromocytoma or paraganglioma. Many of these variants are reported in ExAC (for RET 38%, for SDHA 29%, for SDHB 20%, for SDHC 20% and for VHL 7%). None of our pathogenic SDHD variants are reported in ExAC. Cumulative frequency of these individually rare pathogenic variants in ExAC was 0.00015 (RET) and 0.0002 (SDHA, SDHB, SDHC), four-fold higher than expected from observed population prevalence of MTC or PC/PGL. For RET, the three American Thyroid Association (ATA) risk categories correlated well with groups of variants predicted to have high, moderate, or low/negligible risk of disease penetrance. For SDHB variants present in ExAC, our estimates predict lifetime penetrance of PC/PGL of 23% (95% confidence interval [CI] 12-39%) and lower for SDHA (1.5%, CI 0.5-4.2%) or SDHC (8%, CI 1-33%). Our findings have important implications for genetic counseling and surveillance of subjects carrying pathogenic variants in these genes.