On the interplay of telomere-related genes, nevi and the risk of melanoma

Abstract

Although common melanocytic nevi and dysplastic nevi are strong melanoma risk factors, only a low proportion of subjects carrying multiple nevi develop melanoma. Allelic variation in genes regulating telomere function may increase the risk of progression from nevi to melanoma, after bypassing the senescence state. We conducted a pooled analysis from three case-control studies and one family study from Italy, totaling 794 melanoma cases and 770 unaffected individuals, to examine the association between 517 SNPs mapping to 39 telomere-related genes and melanoma risk. In addition, we explored whether these genes were related to nevi count or the presence of dysplastic nevi in controls. Genotyping was performed using Illumina Infinium custom arrays. SNP association analysis was performed using logistic regression adjusting for age and sex. The role of body mass index was also explored. Meta-analysis of all studies was performed using a random effect model. Gene-based P-values were computed using an adaptive combination of SNP-based P-values. Preliminary results suggest that RECQL4 a gene involved in genome stability, is associated with melanoma risk (gene-based P-value = 0.002). The C allele of the most significant SNP in this gene, rs2721173, increased the risk of melanoma (Odds Ratio (OR): 1.36, 95% Confidence Interval (CI): 1.13-1.63). RTEL1 a gene regulating telomere elongation, was associated with the presence of dysplastic nevi in unaffected subjects (gene-based P = 0.017), with a two-fold increased risk for those carrying the G allele of the most significant SNP in this gene, rs6011002 (OR = 2.19, 95% CI: 1.32-3.65). We are currently examining whether variation in telomere-related genes modifies the association between nevi count and/or dysplastic nevi with melanoma risk. In conclusion, we found suggestive evidence that genes regulating telomere are associated with melanoma risk and dysplastic nevi. If confirmed, these results may identify subgroups of subjects who would benefit from more intensive screening.