Genotype B of Killer Cell Immunoglobulin-Like Receptor is Related with Gastric Cancer Lesions

Abstract

NK cells are important in innate immunity for their capacity to kill infected or cancer cells. The killer cell immunoglobulin-like receptors (KIR) are a family of polymorphic genes with inhibitory and activating functions. The main driving force for gastric cancer (GC) development is a chronic response, which causes an increase of NK cells in the gastric mucosa. The aim of this work was to study polymorphisms in KIR genes in patients with either GC or non-atrophic gastritis (NAG). We studied 242 patients (130 with NAG and 112 with GC) and contrasted with 146 asymptomatic individuals. We analyzed diversity in the content and localization of KIR genes in the different clinical groups studied. Four activating and one inhibitory genes were associated with GC: 2DS1 (OR 3.41), 2DS3 (OR 4.66), 2DS5 (OR 2.25), 3DS1 (OR 3.35) and 2DL5 (OR 3.6). The following were also found as risk factors for GC: Bx genotype (OR 4.2), Bx-Bx centromere-telomere (OR 2.55), cA01|cB03 (OR 36.39) and tB01|tB01 (OR 7.55) gene content and three B motifs (OR 10.9). Polymorphisms in KIR genes were associated with GC and suggest that mutated NK cells may contribute to GC development by increasing gastric mucosa inflammation, leading to constant tissue damage.

Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance

“…The survival benefits in patients with AML that have received grafts with KIR B-haplotypes have guided the selection of aKIR-rich donors for unrelated haploidentical stem cell transplantation in the past decade (29); however, in general, the interaction of aKIR with their HLA ligands renders NKcs hyporesponsive (15,16), and increases susceptibility to cancer and worsen patients' outcomes (24,25). In line with results observed in solid and hematologic malignances (25)(26)(27)(28), data described in this article support a detrimental role for telomeric activating KIR2DS1, KIR2DS3, KIR2DS4full, KIR2DS5, and KIR3DS1 receptors in solid cancer immune surveillance, apparently by increasing the sensitivity of educated NKcs to tumor-induced CD226 downmodulation (3).…”

“…In contrast to inhibitory receptors, aKIR signaling, specifically KIR2DS1 in HLA-C2 homozygous individuals, renders NKcs hyporesponsive, a mechanism that has possibly evolved to prevent autoreactivity (15,16). Apparently, aKIR/self-HLA interactions have detrimental effects on the tumor immune surveillance of NKcs (24), with aKIR richer B-haplotypes showing higher susceptibility to cancer and/or worse outcomes (24)(25)(26)(27)(28). A higher frequency of aKIRs or Bx centromeric and telomeric genotypes has been associated with gastric cancer (26), non-Hodgkin lymphoma (27), and childhood acute lymphoblastic leukemia (28).…”

“…Apparently, aKIR/self-HLA interactions have detrimental effects on the tumor immune surveillance of NKcs (24), with aKIR richer B-haplotypes showing higher susceptibility to cancer and/or worse outcomes (24)(25)(26)(27)(28). A higher frequency of aKIRs or Bx centromeric and telomeric genotypes has been associated with gastric cancer (26), non-Hodgkin lymphoma (27), and childhood acute lymphoblastic leukemia (28). Those genotypes are also associated with poorer prognosis in non-Hodgkin lymphoma (27), higher frequency of minimal residual disease after treatment in childhood acute lymphoblastic leukemia (25), or significantly adverse survival in patients with hematologic malignancies after hematopoietic stem cell transplantation from unrelated donors with NKs educated by aKIRs (24).…”

The Role of Gastric Mucosal Immunity in Gastric Diseases

“…In innate immune response, NK cells can play the role of innate immune response, and its mutation is closely related to the risk of gastric cancer. The activity of NK cells by killer cell immunoglobulin-like receptor (KIR), whose gene mutations can cause the mutation of NK cell activity to aggravate the inflammatory reaction of the gastric mucosa and the occurrence of gastric mucosa damage, eventually leads to gastric cancer [22,23]. NOD1 is a sensor of intracellular innate immunity.…”

The influence of ACYP2 polymorphisms on gastrointestinal cancer susceptibility in the Chinese Han population

“…This can result in genomic instability and chromosomal abnormalities, which can promote carcinogenesis (Duensing & Münger, 2001). It has been reported that telomere-related genes Killer Immunoglobulin-like Receptor (KIR) (Hernandez et al, 2018), protection of telomeres 1 (POT1), telomerase reverse transcriptase (TERT), and telomeric repeat binding factor 2 (TERF2) (Hosgood, Cawthon, He, Chanock, & Lan, 2009) were associated with digestive cancer risk. But the relationship between ACYP2 gene polymorphism and the risk of GI tumors has not been reported.…”