ABSTRACT
Killer cell immunoglobulin-like receptors (KIR) consists of activating and inhibitory genes are essential for natural killer cell education. To determine the association of KIRs with susceptibility to invasive Breast cancer (BC), genotyping of 16 KIRs was performed by sequence-specific primers-polymerase chain reaction in 226 confirmed cases of BC with defined estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status and 226 healthy controls (CNs). We observed a lower frequency of 2DL1 and 2DS4del along with increased frequency of 2DS4fl in cases compared to CNs. Further analysis revealed a higher frequency of KIR2DL2, 2DS1, 2DS2,3DS1 in ER+ cases, 2DL2, 2DL5 in PR+ and 2DL1 in HER2+ cases compared to CNs. The detrimental role of KIR2DS4fl was observed in ER+ and PR+ cases whereas 2DS4del confers protection against ER+, PR+, and HER2+ cases. We noted the predisposing role of Bx genotype, KIR2DS1, 2DS2, 2DS5, 2DL2, 2DL5 for lymphatic invasion in ER+ cases along with a higher rate of lymph node metastasis (LNM) in carriers of Bx genotype and KIR2DS1 in ER+ cases. We suggest a link between B haplotype associated genes with the increased risk of lymphatic invasion and LNM, particularly in ER+ cases of BC.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Gene Frequency , Polymorphism, Genetic , Receptors, KIR/genetics , Adult , Aged , Breast Neoplasms/pathology , Female , Haplotypes , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Receptor, ErbB-2/genetics , Receptors, Estrogen/genetics , Receptors, Progesterone/geneticsABSTRACT
Killer-cell immunoglobulin-like receptors (KIR) are essential for acquiring natural killer (NK) cell effector function, which is modulated by a balance between the net input of signals derived from inhibitory and activating receptors through engagement by human leukocyte antigen (HLA) class I ligands. KIR and HLA loci are polygenic and polymorphic and exhibit substantial variation between individuals and populations. We attempted to investigate the contribution of KIR complex and HLA class I ligands to the genetic predisposition to lung cancer in the native population of southern Iran. We genotyped 16 KIR genes for a total of 232 patients with lung cancer and 448 healthy controls (HC), among which 85 patients and 178 HCs were taken into account for evaluating combined KIR-HLA associations. KIR2DL2 and 2DS2 were increased significantly in patients than in controls, individually (OR 1.63, and OR 1.42, respectively) and in combination with HLA-C1 ligands (OR 1.99, and OR 1.93, respectively). KIR3DS1 (OR 0.67) and 2DS1 (OR 0.69) were more likely presented in controls in the absence of their relative ligands. The incidence of CxTx subset was increased in lung cancer patients (OR 1.83), and disease risk strikingly increased by more than fivefold among genotype ID19 carriers (a CxTx genotype that carries 2DL2 in the absence of 2DS2, OR 5.92). We found that genotypes with iKIRs > aKIRs (OR 1.67) were more frequently presented in lung cancer patients. Additionally, patients with lung cancer were more likely to carry the combination of CxTx/2DS2 compared to controls (OR 2.04), and iKIRs > aKIRs genotypes in the presence of 2DL2 (OR 2.05) increased the likelihood of lung cancer development. Here we report new susceptibility factors and the contribution of KIR and HLA-I encoding genes to lung cancer risk, highlighting an array of genetic effects and disease setting which regulates NK cell responsiveness. Our results suggest that inherited KIR genes and HLA-I ligands specifying the educational state of NK cells can modify lung cancer risk.