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Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK
  1. Anne E Cust1,
  2. Mark Harland2,
  3. Enes Makalic1,
  4. Daniel Schmidt1,
  5. James G Dowty1,
  6. Joanne F Aitken3,
  7. Chantelle Agha-Hamilton4,
  8. Bruce K Armstrong5,
  9. Jenny H Barrett2,
  10. May Chan2,
  11. Yu-Mei Chang2,
  12. Joanne Gascoyne2,
  13. Graham G Giles1,6,
  14. Elizabeth A Holland4,
  15. Richard F Kefford4,
  16. Kairen Kukalizch2,
  17. Johanna Lowery7,
  18. Juliette A Randerson-Moor2,
  19. Helen Schmid4,
  20. Claire F Taylor8,
  21. Linda Whitaker2,
  22. John L Hopper1,
  23. Julia A Newton-Bishop2,
  24. Graham J Mann4,
  25. D Timothy Bishop2,
  26. Mark A Jenkins1
  1. 1Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, The University of Melbourne, Melbourne, Australia
  2. 2Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine (LIMM), University of Leeds, Leeds, UK
  3. 3Viertel Centre for Research in Cancer Control, Cancer Council Queensland, Brisbane, Australia
  4. 4Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Sydney, Australia
  5. 5Sydney School of Public Health, The University of Sydney, Sydney, Australia
  6. 6Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  7. 7Mutation Detection Facility, Cancer Research UK, St James's University Hospital, Leeds, UK
  8. 8Genomics Facility, Leeds Cancer Research UK Centre, University of Leeds, Leeds, UK
  1. Correspondence toDr Anne E Cust, Cancer Epidemiology and Services Research, Sydney School of Public Health, Building D02, The University of Sydney, NSW 2006 Australia; anne.cust{at}


Background CDKN2A mutations confer a substantial risk of cutaneous melanoma; however, the magnitude of risk is uncertain.

Methods The study estimated the hazard ratio (HR) and the average age specific cumulative risk (ie, penetrance) of reported melanoma for CDKN2A mutation carriers in case families using a modified segregation analysis of the first and higher degree relatives of 35 population-based cases. The study sample included 223 relatives of 13 melanoma cases diagnosed when aged 18–39 years from Melbourne, Sydney and Brisbane, Australia, and 322 relatives of 22 melanoma cases diagnosed at any age from Yorkshire, UK.

Results The estimated HR for melanoma for mutation carriers relative to the general population decreased with regions of increasing ambient ultraviolet (UV) irradiance, being higher for the UK than Australia (87, 95% CI 50 to 153 vs 31, 95% CI 20 to 50, p=0.008), and across Australia, 49 (95% CI 24 to 98) for Melbourne, 44 (95% CI 22 to 88) for Sydney, and 9 (95% CI 2 to 33) for Brisbane (p=0.02). Penetrance did not differ by geographic region. It is estimated that 16% (95% CI 10% to 27%) of UK and 20% (95% CI 13% to 30%) of Australian CDKN2A mutation carriers would be diagnosed with melanoma by age 50 years, and 45% (95% CI 29% to 65%) and 52% (95% CI 37% to 69%), respectively, by age 80 years.

Conclusions Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.

  • Melanoma
  • penetrance
  • CDKN2A
  • risk
  • genetic susceptibility
  • Cancer: dermatological
  • genetic epidemiology

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  • Funding The Australian Melanoma Family Study received funding from the National Health and Medical Research Council of Australia (NHMRC) (project grants 107359, 211172, 566946 and Program Grant 402761 to GJM and RFK); project grants from the Cancer Councils New South Wales (77/00, 06/10), Victoria and Queensland (371); and the US National Institutes of Health (via RO1 grant CA-83115-01A2 to the international Melanoma Genetics Consortium (GenoMEL)). AEC is the recipient of an NHMRC public health postdoctoral fellowship (520018) and received a Victorian Cancer Agency Early Career Seed Grant (ECSG07_010). BKA's research was supported by a University of Sydney Medical Foundation Program Grant and JLH is an Australia Fellow of the NHMRC. This research was funded in part by Cancer Research UK (C588/A4994, C588/A10589 C8216/A6129) and by the National Institute of Health (CA83115). UK study recruitment was facilitated by the UK National Cancer Research Network.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of The University of Melbourne, The University of Sydney, Cancer Council Queensland, Cancer Council Victoria, and the University of Leeds.

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