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Natural Killer (NK) cells have antigen-independent tumor cytotoxicity and can control tumor growth and dissemination. The killer immunoglobulin-like receptors (KIRs) participate in NK cells’ recognition of targets. KIRs are a family of ~15 closely linked highly polymorphic genes. KIR2DS4 had been shown to be able to activate NK function against melanoma cells in vitro. We sequenced KIR2DS4 to investigate its effect on melanoma risk in a population of 617 subjects, including 150 melanoma cases and 150 healthy controls from a case-control study, and 103 cases and 214 unaffected relatives from 60 melanoma-prone families from the same area. KIR2DS4 has a common deletion variant (A197) that results in a soluble KIR molecule due to the creation of a stop codon prior to the transmembrane domain. The A197 allele was negatively associated with melanoma risk after adjustment for age and sex (OR=0.41, 95% CI=0.2-0.8, and OR=0.55, 95% CI=0.2-1.8, in the case-control and family study, respectively). We conducted LD analysis between KIR2DS4 and the other KIR genes in 320 independent chromosomes from the CEPH families and found that KIR2DS4 was in strong LD with KIR2DL4. We sequenced KIR2DL4 in 199 melanoma cases and 187 healthy controls. Neither KIR genes was associated with melanoma risk factors or melanoma characteristics in our population. KIR2DL4 alleles have either 9A or 10A at the end of exon 6 which codes for the transmembrane domain. The 10A allele with 10 adenine bases encodes the full length receptor; the 9A allele has only 9 adenines resulting in a premature stop codon in the first cytoplasmic exon. The 9A alleles were in strong LD with the truncated KIR2DS4 allele (A197), and conferred protection against melanoma risk (OR = 0.42, 95% CI=0.3-0.7, p<0.001). The protective effect of the 2DL4 9A alleles was stronger than the effect of the 2DS4 A197. In fact, subjects who carried only the A197 allele and no 9A alleles showed no significant protection (OR=0.56, 95% CI= 0.2-1.5). HLA-G appears to be a ligand for KIR2DL4 and is expressed in ~30% of surgically removed melanoma lesions. We measured circulating HLA-G (cHLA-G) in subjects’ plasma, and found that presence of cHLA-G was not associated with melanoma risk, but within the 75 subjects with detectable levels, the risk increased with increasing cHLA-G (OR=2.6, 95%CI=1.1-6.2, p=0.03). cHLA-G did not modify the association between KIR2DL4 and melanoma risk. We are exploring mechanisms potentially responsible for the protective effect of the 9A allele. Increased knowledge of KIRs’ function and their association with melanoma risk may suggest new strategies for therapy or secondary prevention.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA