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. 2022;31(6):532-539.
doi: 10.1159/000524656. Epub 2022 May 10.

Clinical Impact of KIR2DS3 and KIR2DL3 Genes in Neuroblastoma Patients

Gülay Sezgin  1 , Özlem Görüroğlu Öztürk  2 , Ayşe Özkan  1 , Serhan Küpeli  1 , İbrahim Bayram  1
Affiliations

Clinical Impact of KIR2DS3 and KIR2DL3 Genes in Neuroblastoma Patients

Gülay Sezgin et al. Med Princ Pract. 2022.

Abstract

Objective: Neuroblastoma is a common fatal tumor of childhood. Natural killer (NK) cells can exert direct cytotoxicity on tumor cells. The killer immunoglobulin-like receptor (KIR) family of NK cell receptors is involved in activation/inhibition of NK cells. In the KIR gene cluster, six of them (3DS1, 2DS1-5) encode receptors triggering activation, while seven of them (3DL1-3, 2DL1-3, 2DL5) encode receptors triggering inhibition. We aimed to assess the distribution of genetic polymorphisms of KIRs on the clinical course of neuroblastoma and provide guidance on potential therapeutic options.

Methods: Our study group included 50 neuroblastoma patients and 100 healthy children as controls. Twenty-eight patients were boys, and twenty-two were girls; median age was 36 months. Fourteen patients had stage 1, 2, 3, or 4S disease, and 36 patients had stage 4 disease. Isolated DNA from the peripheral blood was amplified for sequence-specific oligonucleotide probe analysis of 16 KIR genes. The Fisher's exact test was used to evaluate the variation of KIR gene distribution.

Results: All patients had a lower frequency of KIR2DS3 compared to the control group (p = 0.005). Evaluation of individual KIR genes/genotypes in patients with early stages (stage 1, 2, 3, and 4S) versus stage 4 disease revealed that the frequency of KIR2DS3 was increased in early stages (p = 0.023). Inhibitory KIR2DL3 was increased in the patient group compared to controls (p = 0.038). Furthermore, the frequency of KIR2DL3 was higher in stage 4 neuroblastoma patients compared to the patients with early stages (p = 0.023).

Conclusion: Our data suggest a role for KIR2DS3 and KIR2DL3 in development of neuroblastoma. Thus, modulation of KIR2SD3 and/or KIR2DL3 expression or function might present a novel therapeutic strategy for neuroblastoma.

Keywords: KIRs; Killer immunoglobulin-like receptor genes; Natural killer cells; Neuroblastoma.

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Conflict of interest statement

The authors declare that no competing interests exist.

Figures

Fig. 1
Fig. 1
Comparison of frequencies of KIR genotypes in neuroblastoma patients (N = 50) and controls (N = 100) was estimated by two-tailed Fisher's exact test. A statistically significant difference was found between the patient and control groups in frequency of the inhibitory KIR2DL3 gene *p = 0.038. Activating KIR2DS3 was lower in neuroblastoma patients compared to the control group, **p = 0.005.
Fig. 2
Fig. 2
KIR genotypes in neuroblastoma patients. Framework genes are in gray color, activating KIR genes are in red, inhibitory genes are in green, and pseudogenes are in yellow. The haplotype group and genotype ID and the number of patients are presented on the right side.
Fig. 3
Fig. 3
Comparison of patients with early stages of neuroblastoma versus patients with stage 4 for inhibitory KIR2DL3 *p = 0.044 and for activator KIR2DS3, **p = 0.023 by two-tailed Fisher's exact test.
Fig. 4
Fig. 4
Comparison of stage 4 neuroblastoma patients with controls for inhibitory KIR2DL3 and activator KIR2DS3 genes by Fisher's exact test.
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