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CDKN2A Mutations and Melanoma Risk in the Icelandic Population
  1. Alisa M Goldstein (ag26o{at}nih.gov)
  1. NIH, United States
    1. Simon Stacey (simon.stacey{at}decode.is)
    1. deCODE Genetics, Iceland
      1. Jon Olafsson
      1. Landspitali-University Hospital, Iceland
        1. Gudbjörn Jonsson
        1. deCODE Genetics, Iceland
          1. Agnar Helgason
          1. deCODE Genetics, Iceland
            1. Patrick Sulem
            1. deCODE Genetics, Iceland
              1. Bardur Sigurgeirsson
              1. Landspitali-University Hospital, Iceland
                1. Kristrun Benediktsdottir
                1. Landspitali-University Hospital, Iceland
                  1. Kristin Thorisdottir
                  1. Landspitali-University Hospital, Iceland
                    1. Rafn Ragnarsson
                    1. Landspitali-University Hospital, Iceland
                      1. Jens Kjartansson
                      1. Landspitali-University Hospital, Iceland
                        1. Jelena Kostic
                        1. deCODE Genetics, Iceland
                          1. Gisli Masson
                          1. deCODE Genetics, Iceland
                            1. Kristleifur Kristjansson
                            1. deCODE Genetics, Iceland
                              1. Jeffrey Gulcher
                              1. deCODE Genetics, Iceland
                                1. Augustine Kong
                                1. deCODE Genetics, Iceland
                                  1. Unnur Thorsteinsdottir
                                  1. deCODE Genetics, Iceland
                                    1. Thorunn Rafnar (thorunn.rafnar{at}decode.is)
                                    1. deCODE Genetics, Iceland
                                      1. Margaret A Tucker (tuckerp{at}mail.nih.gov)
                                      1. National Cancer Institute, United States
                                        1. Kari Stefansson
                                        1. deCODE Genetics, Iceland

                                          Abstract

                                          Background: Germline CDKN2A mutations have been observed in 20-40% of high-risk melanoma-prone families, however little is known about their prevalence in population-based series of melanoma cases and controls.

                                          Methods: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry-ascertained melanoma cases and 691 population-based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.

                                          Results: We identified a novel germline variant, G89D that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head & neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.

                                          Conclusions: This population-based study of Icelandic melanoma cases and controls showed a frequency of disease-related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consists of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population-based estimates of CDKN2A mutation frequencies are available.

                                          • CDKN2A
                                          • G89D
                                          • melanoma
                                          • pancreatic cancer
                                          • population based

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