CDKN2A Mutations and Melanoma Risk in the Icelandic Population

Alisa M Goldstein ^1*, Simon Stacey ², Jon Olafsson ³, Gudbjörn Jonsson ², Agnar Helgason ², Patrick Sulem ², Bardur Sigurgeirsson ³, Kristrun Benediktsdottir ³, Kristin Thorisdottir ³, Rafn Ragnarsson ³, Jens Kjartansson ³, Jelena Kostic ², Gisli Masson ², Kristleifur Kristjansson ², Jeffrey Gulcher ², Augustine Kong ², Unnur Thorsteinsdottir ², Thorunn Rafnar ², Margaret A Tucker ⁴ and Kari Stefansson ²

¹ NIH, United States
² deCODE Genetics, Iceland
³ Landspitali-University Hospital, Iceland
⁴ National Cancer Institute, United States

^* To whom correspondence should be addressed. E-mail: ag26o{at}nih.gov.

Accepted 9 December 2007

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.

Keywords: CDKN2A, G89D, melanoma, pancreatic cancer, population based

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