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Original article
Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents
  1. Alisa M Goldstein1,
  2. May Chan2,
  3. Mark Harland2,
  4. Nicholas K Hayward3,
  5. Florence Demenais4,
  6. D Timothy Bishop2,
  7. Esther Azizi5,
  8. Wilma Bergman6,
  9. Giovanna Bianchi-Scarra7,
  10. William Bruno7,
  11. Donato Calista8,
  12. Lisa A Cannon Albright9,
  13. Valerie Chaudru4,
  14. Agnes Chompret10,
  15. Francisco Cuellar11,
  16. David E Elder12,
  17. Paola Ghiorzo7,
  18. Elizabeth M Gillanders13,
  19. Nelleke A Gruis6,
  20. Johan Hansson14,
  21. David Hogg15,
  22. Elizabeth A Holland16,
  23. Peter A Kanetsky17,
  24. Richard F Kefford16,
  25. Maria Teresa Landi1,
  26. Julie Lang18,
  27. Sancy A Leachman19,
  28. Rona M MacKie18,
  29. Veronica Magnusson14,
  30. Graham J Mann16,
  31. Julia Newton Bishop2,
  32. Jane M Palmer3,
  33. Susana Puig11,
  34. Joan A Puig-Butille20,
  35. Mitchell Stark3,
  36. Hensin Tsao21,
  37. Margaret A Tucker1,
  38. Linda Whitaker2,
  39. Emanuel Yakobson22,
  40. The Lund Melanoma Study Group23,
  41. and the Melanoma Genetics Consortium (GenoMEL)
  1. 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA
  2. 2Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds, UK
  3. 3Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  4. 4INSERM, U794, Université d’Evry, Evry, France
  5. 5Department of Dermatology, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
  6. 6Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
  7. 7Department of Oncology, Biology, and Genetics, University of Genova, Genova, Italy
  8. 8Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy
  9. 9Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, USA
  10. 10Service de Génétique, Institut Gustave Roussy, Villejuif, France
  11. 11Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS (Institut de Investigació Biomèdica August Pi Suñe), Barcelona, Spain
  12. 12Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  13. 13Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, DHHS, Baltimore, Maryland, USA
  14. 14Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden
  15. 15Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontaria, Canada
  16. 16Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, New South Wales, Australia
  17. 17Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  18. 18Department of Medical Genetics, University of Glasgow, Glasgow, UK
  19. 19Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
  20. 20Genetics Service, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS (Institut de Investigació Biomèdica August Pi Suñe), Barcelona, Spain
  21. 21Wellman Center for Photomedicine, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
  22. 22Molecular Cell Biology Laboratory, Department of Internal Medicine C, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  23. 23Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden
  1. Correspondence to:
 Dr A M Goldstein
 Genetic Epidemiology Branch/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd. MSC 7236, Bethesda, MD 20892-7236, USA; goldstea{at}exchange.nih.gov

Abstract

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.

Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.

Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.

Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

  • ARF, alternate reading frame
  • CMM, cutaneous malignant melanoma
  • MPM, multiple primary melanoma
  • melanoma
  • CDKN2A
  • multiple primary melanomas
  • pancreatic cancer

https://doi.org/10.1136/jmg.2006.043802

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    Footnotes

    • Published Online First 11 August 2006

    • Funding: This research was supported in part by the intramural research programme of the National Institutes of Health, NCI, DCEG and NHGRI. This work was also partially supported by research grants 1 RO1 CA83115-01A2 “Genetic epidemiology of melanoma” from the National Cancer Institute (DEE); RO1 CA88363 from NCI (NH), National Health and Medical Research Council of Australia (Brisbane group); R01 CA102422 from NCI (LACA), the Tom C Mathews Jr Familial Melanoma Research Clinic, the Huntsman Cancer Foundation (Utah group); Cancer Research UK (Leeds group); grants 01/1546 and 03/0019 from Fondo de Investigaciones Sanitarias, V2003-REDC03/03 and /07, a personal grant to Francisco Cuellar CONACYT, Personal Scholarship 152256/158706, Mexico City, Mexico (Barcelona group); FIRB RBNE0149752001 and COFIN 2004/061840_003 (GB-S; Genoa group); The Swedish Cancer Society: research grants 4860-B05-03XAC, 5012-B05-01PAF, The Swedish Research Council: research grant K2006-74X-20141-01-3 and grants from The Radiumhemmet Research Funds (JH; Stockholm group); Programme Hospitalier de Recherche Clinique Régional d’Ile de France grant AP-HP AOR 01 091 (Marie-Francoise Avril); Research grants and scholarships of the Australian National Health and Medical Research Council (G J M and R F K), The Cancer Councils of Australia, the Australian Cancer Research Foundation, the Melanoma Foundation and Cancer Research Fund of the University of Sydney (Sydney group). P A K was supported by a National Cancer Institute Preventive Oncology Academic Award (K07 CA80700). Some data collection for this publication was assisted by the Utah Cancer Registry supported by NIH Contract NO1-PC-35141, SEER Program, with additional support from the Utah Department of Health and the University of Utah. Partial support for all datasets within the Utah Population Database (UPDB) was provided by the University of Utah Huntsman Cancer Institute.

    • Competing interests: None.

    • Authors from Lund Melanoma Study Group:

      Lund Cancer Center Department of Oncology, University Hospital, Lund, Sweden (Christian Ingvar, Ake Borg, Johan Westerdahl, Anna Masback, Hakan Olsson)

      Additional authors from GenoMEL listed by group/centre:

      Barcelona: Dermatology Department (Josep Malvehy) and Genetics Service (Celia Badenas, Remedios Cervera), Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; Dermatology Department, Hospital Arnau de Vilanova, Universitat de Lleida, Lleida, Spain (Rosa Martí); Genetic Counseling of Cancer, Hospital Sant Joan, Universitat Rovira i Virgili, Reus, Spain and ICO, Hospital Trueta, Girona, Spain (Joan Brunet-Vidal); Boston: Massachusetts General Hospital, Boston, MA (Guang Yang); Brisbane: Queensland Institute of Medical Research (Nicholas Martin, David Whiteman, Adele Green) and Queensland Cancer Fund (Joanne Aitken), Brisbane, Australia; Emilia-Romagna: Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy (Paola Minghetti); Genoa: Dipartimento di Oncologia, Biologia e Genetica, Universita degli Studi di Genova, Vle Benedetto XV, 6, 16132 Genova, Italy (Michela Mantelli, Lorenza Pastorino, Sabina Nasti, Sara Gargiulo), Istituto Nazionale per la Ricerca sul Cancro (IST), Largo Rosanna Benzi, 10, 16132 Genova, Italy (Sara Gliori); Leeds: Genetic Epidemiology Division, Cancer Research UK Clinical Centre, Leeds (Sushila Mistry, Juliette Randerson-Moor); Leiden: Leiden University Medical Center (Femke A de Snoo, Jeanet AC ter Huurne, Jasper van der Rhee, Leny van Mourik, Frans van Nieuwpoort), STOET, The Netherlands Foundation for the Detection of Hereditary Tumors (Clasine van der Drift), Leiden, The Netherlands; Paris: Service de Génétique, Institut Gustave Roussy, Villejuif (Brigitte Bressac-de Paillerets), AP-HP-Hopital Cochin, Université Réné Descartes, Paris (Marie-Francoise Avril), French Hereditary Melanoma Study Group: Drs F Grange, B Sassolas, F Boitier, J Chevrant-Breton, C Lasset, C Dugast, P Vabres, France; Philadelphia: Department of Genetics (Arupa Ganguly), Department of Dermatology (Michael Ming), Department of Pathology and Laboratory Medicine (Patricia Van Belle), University of Pennsylvania, Philadelphia, PA, USA;

      Stockholm: Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden (Anton Platz, Suzanne Egyhazi, Rainer Tuominen, Diana Linden); Sydney: Westmead Institute for Cancer Research, Sydney, Australia (Helen Schmid);

      Tel-Aviv: Department of Dermatology (Alon Scope, Felix Pavlotsky), The Susanne Levy Oncogenetics Unit (Eitan Friedman), Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Israel; Utah: Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT (Mark Eliason).

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