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CDKN2A Common Variants and Their Association with Melanoma Risk: A Population-Based Study

Tadeusz Dbniak¹, Rodney J. Scott⁴, Tomasz Huzarski¹, Tomasz Byrski¹, Andrzej Rozmiarek⁵, Bogusaw Dbniak⁶, Elbieta Zauga², Romuald Maleszka², Józef Kadny³, Bohdan Górski¹, Cezary Cybulski¹, Jacek Gronwald¹, Grzegorz Kurzawski¹ and Jan Lubinski¹

Departments of ¹ Genetics and Pathology, International Hereditary Cancer Center and ² Dermatology and Venerology, Pomeranian Medical University; ³ III Department of Surgery, Pomeranian Academy of Medicine, Szczecin, Poland; ⁴ Discipline of Medical Genetics, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; ⁵ Regional Hospital, Zielona Góra, Poland; ⁶ Regional Hospital, Gorzow Wielkopolski, Poland

Requests for reprints: Tadeusz Dbniak, Poabska 4, 70-115 Szczecin, Poland. Phone: 48-91-4661533; Fax: 48-91-4661533; E-mail: debniak{at}wp.pl.

The population frequencies of the CDKN2A variants remain undetermined. In Poland there are three common variants of CDKN2A: an alanine to threonine substitution (A148T), Nt500c>g and Nt540c>t, which have been detected in other populations. To establish if they are associated with an increased malignant melanoma (MM) risk we did an association study based on genotyping 471 patients with MM and 1,210 random control subjects from the same Polish population. We found a significantly increased frequency of the A148T variant among patients with MM (7.0%) in comparison with the general population (2.9%). The incidence of the A148T variant remained greater in both unselected and familial melanoma subgroups. A statistically significant positive association was seen for unselected MM (odds ratio, 2.529; P = 0.0003), especially in patients diagnosed under 50 years of age (odds ratio, 3.4; P = 0.0002). The A148T carrier population (heterozygous G/A alleles) was more likely to have a relative with malignancy compared with the noncarrier population (57% versus 36%, respectively; P = 0.03). Further examination of the CDKN2A promoter sequence done in 20 melanoma patients with the A148T change (heterozygous G/A alleles) and 20 patients with MM without this alteration identified it was in linkage disequilibrium with a polymorphism in the promoter region at position P-493. We found no statistically significant overrepresentation of the Nt500c>g and the Nt540c>t polymorphisms in the Polish melanoma population. In conclusion, the A148T variant of the CDKN2A gene seems to be associated with an increased risk of development of MM. Additional studies are required to confirm whether this particular change is associated with increased risk of other nonmelanoma malignancies.

Key Words: malignant melanoma • CDKN2A • A148T variant • Nt500c>g • Nt540c>t • P-493

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