Reduced DNA repair capacity has been proposed as a predisposing factor for melanoma. We comprehensively evaluated 1465 genetic variants across 60 DNA repair-related pathway genes in relation to melanoma risk in a nested case-control study of 218 melanoma cases and 218 matched controls within the Nurses’ Health Study (NHS). We then genotyped the two variants with the smallest P value in two replication sets: 184 melanoma cases and 184 matched controls in the Health Professionals Follow-Up Study (HPFS); and 183 melanoma cases and 183 matched controls in the NHS. The SNP rs3219125 in the PARP1 gene was significantly associated with melanoma risk in the discovery set (odds ratio (OR) 3.14; 95% confidence interval (CI) 1.70-5.80) and in the HPFS replication set (OR, 1.92; 95%CI, 1.05-3.54), but not in the NHS replication set (OR, 1.07; 95%CI, 0.58-1.97), while in the joint analysis, the OR was 1.89 (95%CI, 1.34-2.68) for this polymorphism. Given that DNA repair protects against UV-induced melanoma, the sun-exposed body sites are more prone to insufficiency in DNA repair capacity. Thus, we further conducted subgroup analysis of this SNP by body sites and found that the increased risk of this variation was more pronounced among patients with lesions in head/neck (OR, 3.19; 95% CI, 1.77-5.73 for head/neck, and OR, 1.54; 95% CI, 1.03-2.30 for other sites, P value for heterogeneity test = 0.036), which further suggested the involvement of this locus in the etiology of melanoma via its influence on DNA repair capacity. In addition, there were significantly fewer head/neck melanoma cases in the NHS replication set (20.4% in the discovery set, 28.1 % in the HPFS replication set, and 9.5% in the NHS replication set, P < 0.001), which may explain the failure of the replication in the NHS replication set. In conclusion, our findings implicate the PARP1 variant in the etiology of melanoma cancer, especially for sites with high sun exposure. Further work is needed to replicate these results and clarify the mechanism by functional studies.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):B15.
- Copyright © July 15, 2010, American Association for Cancer Research