Abstract 1353: KIR copy-number variation and cutaneous melanoma risk.

Abstract

Abstract Prevention of cutaneous malignant melanoma requires the identification and clearance of abnormal, pre-cancerous cells by the immune system. Central to this immune surveillance is the interplay between KIR receptors present on natural killer cells and their HLA ligands expressed on target cells. Like HLA, the KIR genes are highly polymorphic. They encode both activating receptors (that trigger NK-cell mediated killing), and inhibitory receptors (important in NK cell education and self-tolerance). Many of the KIR genes occur as copy number variants, and we hypothesize that inter- individual variability in KIR copy number is associated with melanoma risk. A random sample of cases and controls within the large, population-based Minnesota Skin Health Study were selected for examination (84 cases and 87 controls). Using Luminex technology and genomic DNA isolated from subject buccal cells we tested for the presence or absence of specific KIR genes (KIR3DL1, KIR2DS1, KIR2DL2, KIR2DL3, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4 {truncating allele}, KIR2DS5, KIR2DS1). In addition to investigating each gene as a melanoma risk factor, we created an integrated locus score for 2DL2/DL3 and 3DL1/DS1, reflecting the typical mutual exclusivity of these genes at their respective loci. Results: Homozygous deletion of the activating KIR gene 2DS1 was associated with both an increasing number of nevi (p<0.04), and increased melanoma risk (OR 2.2, 95% CI 1.2 - 4.3). Similarly, at the shared 3DL1/3DS1 locus, absence of the activating KIR3DS1 gene was significantly associated with increased melanoma risk (OR 2.0, 95% CI 1.0 - 3.3), and a borderline significant increase in the number of nevi (p<0.07). In contrast, at the KIR2DL2/2DL3 locus, which encodes two inhibitory KIR alleles, our data suggest that a lack of diversity at this locus may be more important than the presence or absence of either gene; individuals homozygous for either 2DL2 or 2DL3 were at increased risk for both nevi (p<0.03), and melanoma (OR 1.8, 95% CI 1.0 - 3.4) relative to those who had both 2DL2 and 2DL3. These novel analyses at the complex KIR locus indicate that absence of certain activating KIR receptors, and balance in diversity of KIR inhibitory receptors are important determinants of cutaneous melanoma risk. Citation Format: Heather H. Nelson, Karin Vineretsky, DeAnn Lazovich. KIR copy-number variation and cutaneous melanoma risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2013-1353