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Cancer genetics
Original article
Bayesian approach to determining penetrance of pathogenic SDH variants
  1. Diana E Benn1,2,
  2. Ying Zhu1,2,3,
  3. Katrina A Andrews4,
  4. Mathilda Wilding3,
  5. Emma L Duncan5,6,7,
  6. Trisha Dwight1,2,
  7. Richard W Tothill8,9,
  8. John Burgess10,
  9. Ashley Crook3,
  10. Anthony J Gill2,11,
  11. Rodney J Hicks8,9,
  12. Edward Kim1,2,
  13. Catherine Luxford1,
  14. Helen Marfan12,
  15. Anne Louise Richardson1,
  16. Bruce Robinson1,2,13,
  17. Arran Schlosberg2,
  18. Rachel Susman12,
  19. Lyndal Tacon1,13,2,
  20. Alison Trainer8,9,
  21. Katherine Tucker14,
  22. Eamonn R Maher4,
  23. Michael Field3,
  24. Roderick J Clifton-Bligh1,13,2
  1. 1 Hormones and Cancer, Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  2. 2 Department of Medicine, University of Sydney, Sydney, New South Wales, Australia
  3. 3 Department of Cancer Services, Northern Sydney Local Health District Familial Cancer Service, Royal North Shore Hospital, Saint Leonards, New South Wales, Australia
  4. 4 Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre and Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK
  5. 5 School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
  6. 6 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  7. 7 Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  8. 8 Department of Oncology, The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  9. 9 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  10. 10 Faculty of Medicine, University of Tasmania, Hobart, Tasmania, Australia
  11. 11 Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  12. 12 Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
  13. 13 Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, USA
  14. 14 Department of Clinical Genetics, Prince of Wales Hospital, Randwick, New South Wales, Australia
  1. Correspondence to Dr Roderick J Clifton-Bligh, Department of Endocrinology, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; jclifton{at}med.usyd.edu.au

Abstract

Background Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows 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 two cohorts for succinate dehydrogenase subunits A, B and C (SDHA–C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).

Methods Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).

Results Pathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA–C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants.

Conclusion Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.

  • pheochromocytoma
  • paraganglioma
  • succinate dehydrogenase
  • penetrance
  • pathogenic variant

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jmedgenet-2018-105427

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    Footnotes

    • Contributors MF and RJC-B conceived the study and wrote the manuscript. DEB, TD, CL, ALR, BR and RJC-B were responsible for curating the genetic test results for Cohort 1, and KAA and ERM were responsible for Cohort 2. Additional oversight of the clinical cohorts was provided by JB, AC, AJG, RJH, HM, RS, LT, AT, and KT. DEB, MW and EK confirmed pathogenicity for each variant. DEB, YZ, MF and RJC-B performed the initial analyses, with input from ELD, RWT and AS. All authors had full access to the data, and contributed to review of the manuscript.

    • Funding This work was supported by NHMRC Project 1108032 to DEB, RT, ED, TD, KT, AJG, BGR, RH, AT and RJC-B and Hillcrest Foundation (Perpetual Trustees) to DB and TD.

    • Competing interests None declared.

    • Patient consent Not requried.

    • Ethics approval Northern Sydney Local Health District Human Research Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.