Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells.

Autor:	Vineretsky KA; Division of Environmental Health Sciences, School of Public Health, University of Minnesota, Minneapolis, Minnesota., Karagas MR; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire., Christensen BC; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire., Kuriger-Laber JK; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Perry AE; Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire., Storm CA; Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire., Nelson HH; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota. hhnelson@umn.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2016 Jan 15; Vol. 76 (2), pp. 370-6. Date of Electronic Publication: 2016 Jan 07.
DOI:	10.1158/0008-5472.CAN-15-0547
Abstrakt:	Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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