HLA-G

Gene Summary

Gene:HLA-G; major histocompatibility complex, class I, G
Aliases: MHC-G
Location:6p22.1
Summary:HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:HLA class I histocompatibility antigen, alpha chain G
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Thyroiditis, Autoimmune
  • Smoking
  • Risk Factors
  • Flow Cytometry
  • Thyroid Cancer
  • Bladder Cancer
  • Genotype
  • Genetic Predisposition
  • Transcriptional Activation
  • Staging
  • Polymorphism
  • Tumor Escape
  • Messenger RNA
  • Transcription
  • Tissue Array Analysis
  • B-Cell Lymphoma
  • Tumor Burden
  • RTPCR
  • Major Histocompatibility Complex
  • Reproduction
  • Cervical Cancer
  • Cancer Gene Expression Regulation
  • Histocompatibility Antigens Class I
  • Chromosome 6
  • Gene Expression
  • HLA Antigens
  • Breast Cancer
  • 3' Untranslated Regions
  • Stomach Cancer
  • Natural Killer Cells
  • Young Adult
  • Reed-Sternberg Cells
  • HLA-G Antigens
  • Vaginal Cancer
  • Biomarkers, Tumor
  • INDEL Mutation
  • Republic of Korea
  • T-Lymphocytes
  • Case-Control Studies
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HLA-G (cancer-related)

Agnihotri V, Gupta A, Kumar R, et al.
Promising link of HLA-G polymorphism, tobacco consumption and risk of Head and Neck Squamous Cell Carcinoma (HNSCC) in North Indian population.
Hum Immunol. 2017; 78(2):172-178 [PubMed] Related Publications
Human leukocyte antigen (HLA-G) is a potent immune-tolerant molecule and has a critical role in various pathological conditions of cancer. The aim of the study was to analyze the association of HLA-G polymorphism as a risk factor in Head and Neck Squamous Cell Carcinoma (HNSCC). The HLA-G polymorphism at 3'UTR 14bp INDEL (rs371194629) and +3142G/C (rs1063320) were studied in 383 HNSCC patients and 383 ethnically similar-aged healthy controls in North Indian population. The genotyping study of two polymorphisms of HLA-G was documented using DNA-PAGE and RFLP-PCR method. 14bp INDEL Del/Ins, Ins/Ins genotype and Ins allele were more pronounced in HNSCC patients in compared to controls. Whereas, +3142 C/C genotype and C allele were associated with risk factors in HNSCC. Furthermore, the dual effect of polymorphisms; both variants (Del/Ins-Ins/Ins & G/C-C/C) carrying loci was significantly (OR=2.78) associated with the disease compared to one variant (Del/Del-G/C or Del/Del-C/C or Ins/Ins-G/G). Moreover, both polymorphisms showed promising link in terms of tobacco influence on HNSCC risk. It can be concluded that this study first time reports that C/C, Del/Ins and Ins/Ins genotype as well as C and Ins allele could be major risk factors with strong impact of tobacco for HNSCC in North Indian population.

Johansen LL, Lock-Andersen J, Hviid TV
The Pathophysiological Impact of HLA Class Ia and HLA-G Expression and Regulatory T Cells in Malignant Melanoma: A Review.
J Immunol Res. 2016; 2016:6829283 [PubMed] Free Access to Full Article Related Publications
Malignant melanoma, a very common type of cancer, is a rapidly growing cancer of the skin with an increase in incidence among the Caucasian population. The disease is seen through all age groups and is very common in the younger age groups. Several studies have examined the risk factors and pathophysiological mechanisms of malignant melanoma, which have enlightened our understanding of the development of the disease, but we have still to fully understand the complex immunological interactions. The examination of the interaction between the human leucocyte antigen (HLA) system and prognostic outcome has shown interesting results, and a correlation between the down- or upregulation of these antigens and prognosis has been seen through many different types of cancer. In malignant melanoma, HLA class Ia has been seen to influence the effects of pharmaceutical drug treatment as well as the overall prognosis, and the HLA class Ib and regulatory T cells have been correlated with tumor progression. Although there is still no standardized immunological treatment worldwide, the interaction between the human leucocyte antigen (HLA) system and tumor progression seems to be a promising focus in the way of optimizing the treatment of malignant melanoma.

Özgül Özdemir RB, Özdemir AT, Oltulu F, et al.
A comparison of cancer stem cell markers and nonclassical major histocompatibility complex antigens in colorectal tumor and noncancerous tissues.
Ann Diagn Pathol. 2016; 25:60-63 [PubMed] Related Publications
Colorectal carcinoma (CRC) is one of the most fatal types of cancer in both women and men, and, unfortunately, patients are often diagnosed at an advanced stage. Cancer stem cells (CSCs) are associated with poor prognosis, metastasis, and recurrence, as well as chemotherapy and radiotherapy resistance. Therefore, different treatment alternatives are needed to facilitate the elimination of CSCs. One such approach is immunotherapy; however, tumor cells can evade immune cells by alteration of the expression patterns of human leukocyte antigens (HLA). In this study, we immunohistochemically investigated the expression patterns of CSC-specific markers CD44, CD133, Nanog, and Oct3/4, and immunosuppressive molecules HLA-G and -E in advanced CRC tumor tissues and noncancerous colon biopsies. We found significantly increased CD44, Nanog, Oct3/4, HLA-G, and HLA-E expression in the CRC tumor tissues compared with the noncancerous colon biopsies. These findings suggest that some tumor cells may be CSC-like and that the increased expression of HLA-G and HLA-E may be considered as an immune-evasive adaptation. Therefore, the nonclassical major histocompatibility complex class Ib antigens HLA-G and HLA-E may be potential targets in the elimination of CRC-CSCs. However, more detailed studies are required to support our findings.

Coelho AV, Moura RR, Crovella S, Celsi F
HLA-G genetic variants and hepatocellular carcinoma: a meta-analysis.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Human leukocyte antigen (HLA)-G is a key tolerogenic molecule mainly expressed in the placenta and is crucial for implantation of the embryo and immunological tolerance of the fetus during pregnancy. However, under pathological conditions, such as cancer or viral infections, HLA-G can be expressed in other tissues. The gene coding for HLA-G (HLA-G, chromosome 6p21.3) presents numerous polymorphisms, some of them influencing its expression. One of the most studied, is the 14 bp ins/del (rs371194629) situated at the 3'-UTR of the gene. The insertion is thought to stabilize HLA-G mRNA. Different studies have analyzed the role of rs371194629 in hepatic injury, with either hepatotropic virus infection (i.e., HBV or HCV) or hepatocellular carcinoma (also induced by viral infection). Results from these studies are heterogeneous, differing with ethnicity and population age, and the role of rs371194629 is unclear. For these reasons, we decided to perform a meta-analysis of these results, concluding that the 14-bp ins/del polymorphism does not significantly contribute to hepatic injury.

Caocci G, Greco M, Fanni D, et al.
HLA-G expression and role in advanced-stage classical Hodgkin lymphoma.
Eur J Histochem. 2016; 60(2):2606 [PubMed] Free Access to Full Article Related Publications
Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.

Swets M, Seneby L, Boot A, et al.
Promoter methylation and mRNA expression of HLA-G in relation to HLA-G protein expression in colorectal cancer.
Hum Immunol. 2016; 77(9):764-72 [PubMed] Related Publications
Expression of human leukocyte antigen-G (HLA-G) is a suggested mechanism used by tumor cells to escape from host immune recognition and destruction. Advances in the field have made it evident that HLA-G is expressed in different types of malignancies including colorectal cancer (CRC). We analyzed HLA-G expression in 21 low passage CRC cell lines. The level of DNA methylation of the HLA-G gene and the presence of mRNA encoding HLA-G was measured. Moreover, HLA-G protein expression was determined by flow cytometry and immunohistochemistry (IHC). IHC was performed with three different monoclonal antibodies (mAbs) (4H84, MEM-G/1 and MEM-G/2). In addition, HLA-G protein expression was measured in matching primary tumor tissues. RNA analysis using RT-PCR followed by sequencing in 6 samples indicated strong homology of the PCR product with HLA-G3 in 5 samples. In accordance, in none of the cell lines, HLA-G1 expression was detected by flow-cytometry. Furthermore, no association between HLA-G DNA methylation patterns and HLA-G mRNA expression was observed. In addition, different immunohistochemical staining profiles among various anti-HLA-G mAbs were observed. In conclusion, the results of this study show that the HLA-G3 isoform was expressed in some of the CRC cell lines irrespective of the level of DNA methylation of HLA-G.

Seliger B
Role of microRNAs on HLA-G expression in human tumors.
Hum Immunol. 2016; 77(9):760-3 [PubMed] Related Publications
The non-classical human leukocyte antigen G (HLA-G) known to protect the embryo from immune cell destruction leading to fetal maternal tolerance is often overexpressed in human tumors of distinct origin thereby leading to an escape from T and NK cell-mediated immune response. The molecular mechanisms controlling HLA-G expression are complex and involve deregulation at the transcriptional, epigenetic and posttranscriptional level. Using bioinformatics and high through put analyses a number of microRNAs (miRs) have been identified, which were able to bind to the 3' UTR of HLA-G with distinct efficacy. This caused by a downregulation of HLA-G surface expression, which was associated with an increased immune response thereby overcoming the HLA-G-mediated immune tolerance. Reduced expression of HLA-G-specific miRs was associated with tumor progression and metastases and appear to affect directly or indirectly tumor characteristics, such as cell proliferation, apoptosis and resistance to chemotherapy. Recently, an interaction between long non-coding RNAs, such as HOTAIR, and HLA-G-specific miRs has also been demonstrated. This review summarizes the control of HLA-G expression and function by microRNAs as well as its clinical significance.

Gallegos CE, Michelin S, Dubner D, Carosella ED
Immunomodulation of classical and non-classical HLA molecules by ionizing radiation.
Cell Immunol. 2016; 303:16-23 [PubMed] Related Publications
Radiotherapy has been employed for the treatment of oncological patients for nearly a century, and together with surgery and chemotherapy, radiation oncology constitutes one of the three pillars of cancer therapy. Ionizing radiation has complex effects on neoplastic cells and on tumor microenvironment: beyond its action as a direct cytotoxic agent, tumor irradiation triggers a series of alterations in tumoral cells, which includes the de novo synthesis of particular proteins and the up/down-regulation of cell surface molecules. Additionally, ionizing radiation may induce the release of "danger signals" which may, in turn lead to cellular and molecular responses by the immune system. This immunomodulatory action of ionizing radiation highlights the importance of the combined use (radiotherapy plus immunotherapy) for cancer healing. Major histocompatibility complex antigens (also called Human Leukocyte Antigens, HLA in humans) are one of those molecules whose expression is modulated after irradiation. This review summarizes the modulatory properties of ionizing radiation on the expression of HLA class I (classical and non-classical) and class II molecules, with special emphasis in non-classical HLA-I molecules.

Nguyen-Lefebvre AT, Ajith A, Portik-Dobos V, et al.
Mouse models for studies of HLA-G functions in basic science and pre-clinical research.
Hum Immunol. 2016; 77(9):711-9 [PubMed] Related Publications
HLA-G was described originally as a tolerogenic molecule that allows the semiallogeneic fetus to escape from recognition by the maternal immune response. This review will discuss different steps in the study of HLA-G expression and functions in vivo, starting with analyses of expression of the HLA-G gene and its receptors in transgenic mice, and continuing with applications of HLA-G and its receptors in prevention of allograft rejection, transplantation tolerance, and controlling the development of infection. Humanized mouse models have been discussed for developing in vivo studies of HLA-G in physiological and pathological conditions. Collectively, animal models provide an opportunity to evaluate the importance of the interaction between HLA-G and its receptors in terms of its ability to regulate immune responses during maternal-fetal tolerance, survival of allografts, tumor-escape mechanisms, and development of infections when both HLA-G and its receptors are expressed. In addition, in vivo studies on HLA-G also offer novel approaches to achieve a reproducible transplantation tolerance and to develop personalized medicine to prevent allograft rejection.

Zambra FM, Biolchi V, de Cerqueira CC, et al.
Immunogenetics of prostate cancer and benign hyperplasia--the potential use of an HLA-G variant as a tag SNP for prostate cancer risk.
HLA. 2016; 87(2):79-88 [PubMed] Related Publications
Human leukocyte antigen G (HLA-G) is an immunomodulatory molecule with important roles both physiologically as well as an escape mechanism of cancer cells. In this study, we evaluated the impact of eight polymorphisms at the 3' untranslated region (3'UTR) of the HLA-G gene in the development of prostate cancer (PCa) and benign prostatic hyperplasia (BPH). A total of 468 DNA samples of Brazilian men predominantly Euro-descendant with PCa (N = 187), BPH (N = 152) and healthy control individuals (N = 129) were evaluated. The HLA-G 3'UTR region was amplified by polymerase chain reaction (PCR), sequenced and genotyped to identify the 14 bp insertion/deletion (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027A/C (rs17179101), +3035C/T (rs17179108), +3142G/C (rs1063320), +3187A/G (rs9380142) and +3196C/G (rs1610696) polymorphisms. Regression logistic and chi-square tests were performed to verify the influence of single nucleotide polymorphisms (SNPs) in PCa and/or BPH susceptibility, as well as in PCa progression (clinicopathological status). Our data showed the UTR-4 haplotype as a risk factor to PCa in comparison with control [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.39-3.96, P adjusted = 0.003) and BPH groups (OR 1.82, 95% CI 1.15-2.86, P adjusted = 0.030). Further, the 'non-14bp Ins_ + 3142G_+3187A' haplotype (OR 1.56, 95% CI 1.10-2.20, P adjusted = 0.036), the +3003CT genotype (OR 4.44, 95% CI 1.33-4.50, P adjusted = 0.032) and the +3003C allele (OR 2.33, 95% CI 1.38-3.92, P adjusted = 0.016) also conferred susceptibility to PCa. Our data suggest an important influence of HLA-G 3'UTR polymorphisms in PCa susceptibility and support the use of the +3003 variant as a tag SNP for PCa risk.

Lazarte J, Goldraich L, Manlhiot C, et al.
Human Leukocyte Antigen-G Polymorphisms Association With Cancer Post-Heart Transplantation.
Hum Immunol. 2016; 77(9):805-11 [PubMed] Related Publications
BACKGROUND: Post transplantation, a major complication is the development of malignancies. Human Leukocyte Antigen (HLA)-G is a molecule that inhibits the immune system and it is utilized by malignant cells to hide from the immune system. Expression of HLA-G from the donor and recipient cells in transplant patients is regulated by gene variations however, the association between genotype and cancer remains unknown. Our objective was to determine the association between genotype and outcome.
METHODS: Heart transplant recipients (251) and available corresponding donors (196) samples were genotyped for polymorphisms and the association of polymorphisms to outcome was evaluated with parametric hazard regression models.
RESULTS: Risk of cancer was 22% at 10years post-transplantation. The mean follow-up was of 4.9±3.6years. In a multivariable analysis, donor-recipient SNP 3187 matching was identified as a protective factor for cancer (hazard ratio 0.43; 95% confidence interval 0.19-0.93; p=0.03). While coding region allele (haplotype 6) was identified as an independent risk factor (hazard ratio 3.7; 95% confidence interval 1.36-10.06; p=0.01).
CONCLUSION: In this investigation, we identified an association between cancer post-transplantation and HLA-G polymorphisms, which may reveal a pathway for potential diagnostic and therapeutic strategies for cancer post-transplantation.

Garziera M, Catamo E, Crovella S, et al.
Association of the HLA-G 3'UTR polymorphisms with colorectal cancer in Italy: a first insight.
Int J Immunogenet. 2016; 43(1):32-9 [PubMed] Related Publications
This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3'UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a 'protective' role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF = 0.1%) and +3092 G/T (EUR MAF = 0%). This is the first study showing associations between different polymorphisms in the HLA-G 3'UTR and colorectal cancer susceptibility.

Jesionek-Kupnicka D, Bojo M, Prochorec-Sobieszek M, et al.
HLA-G and MHC Class II Protein Expression in Diffuse Large B-Cell Lymphoma.
Arch Immunol Ther Exp (Warsz). 2016; 64(3):225-40 [PubMed] Related Publications
The expression of human leukocyte antigen-G (HLA-G) and HLA class II protein was studied by immunohistochemical staining of lymph nodes from 148 patients with diffuse large B-cell lymphoma (DLBCL) and related to the clinical course of the disease. Negative HLA-G expression was associated with a lower probability of achieving a complete remission (p = 0.04). Patients with negative HLA-G expression tended towards a lower 3-year overall survival (OS) rate compared to those with positive expression of HLA-G (p = 0.08). When restricting the analysis to patients receiving chemotherapy with rituximab, the estimated 3-year OS rate of patients with positive HLA-G expression was 73.3 % compared with 47.5 % (p = 0.03) in those with negative expression. Patients with negative HLA class II expression presented a lower 3-year OS rate compared to subjects with positive expression (p = 0.04). The loss of HLA class II expression (p = 0.05) and belonging to the intermediate high/high IPI risk group (p = 0.001) independently increased the risk of death. HLA class II expression also retained its prognostic value in patients receiving rituximab; the 3-year OS rate was 65.3 % in patients with positive HLA class II expression versus 29.6 % (p = 0.04) in subjects that had loss of HLA class II expression. To our knowledge, for the first time, the expression of HLA-G protein in DLBCL and its association with the clinical course of the disease was demonstrated. Moreover, the link between losing HLA class II protein expression and poor survival of patients treated with immunochemotherapy was confirmed.

Garziera M, Bidoli E, Cecchin E, et al.
HLA-G 3'UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment.
PLoS One. 2015; 10(12):e0144000 [PubMed] Free Access to Full Article Related Publications
An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host's immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3'UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3'UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3'UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3'UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3'UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38-0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26-0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19-5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16-6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3'UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G.

Guan Z, Song B, Liu F, et al.
TGF-β induces HLA-G expression through inhibiting miR-152 in gastric cancer cells.
J Biomed Sci. 2015; 22:107 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mounting evidences have showed the important role of transforming growth factor-β (TGF-β) in immunological surveillance of tumors. Some studies have also indicated human leukocyte antigen (HLA)-G-associated immune escape involving TGF-β management in gastric cancer (GC). However, the mechanism underlying it is unclear. This study aims to verify the correlations between HLA-G and TGF-β, involving the potential targeting of miR-152 on HLA-G.
RESULTS: TGF-β and HLA-G levels were analyzed in blood samples from twenty GC patients with ELISA assays, while TGF-β showed directly proportional to HLA-G levels in GC patients, and TGF-β induced HLA-G up-regulation was also confirmed in GC cell lines. Furthermore, miR-152 expression could be inhibited by TGF-β, and the negative post-transcriptionally regulation of miR-152 on HLA-G was also demonstrated through gain- and loss-of-function studies. Besides, miR-152 overexpression repressed HLA-G up-regulation induced by TGF-β. And, miR-152 expression levels showed inversely proportional to both HLA-G and also TGF-β levels in GC patients.
CONCLUSION: TGF-β could induce HLA-G expression in GC by inhibiting miR-152, involving its negative regulation on HLA-G. Since TGF-β induced HLA-G up-regulation plays important role in immune escape, a potential application of miR-152 was suggested in GC treatment, or miR-152 might be one potential biomarker for GC.

Khorrami S, Rahimi R, Mohammadpour H, et al.
Association of HLA-G*01:01:02:01/G*01:04:01 polymorphism with gastric adenocarcinoma.
Hum Immunol. 2016; 77(2):153-7 [PubMed] Related Publications
Human leukocyte antigen-G (HLA-G) plays an important role in tumor cell escape from immune surveillance and HLA-G polymorphisms might service as a potential risk factor for clinical outcomes in GAC (gastric adenocarcinoma). We investigated the association between HLA-G polymorphisms as well as soluble HLA-G level and accordance of GAC. This case-control study included 100 GAC patients and 102 unrelated Iranian individual's samples as control. The clinical stages ranged from I to IV. PCR-RFLP method was carried out in order to specify the genotypes of the HLA-G gene. Concentrations of sHLA-G in serum were determined with the sHLA-G-specific enzyme linked immunosorbent assay (ELISA) kit. The G*01:04:01 and G*01:01:02:01 alleles were the predominant alleles in GAC patients and healthy controls. The G*01:01:03:01 and G*01:01:08 allele distributions are significantly higher among controls comparing to cases and seem to have protective effect (P value=0.026 and 0.007 respectively). There is a substantial differences in G*01:01:02:01/G*01:04:01 genotype frequencies between cases and controls (OR=2.8, P value<0.001). The G*01:01:03:01/G*01:04:01 and G*01:01:02:01/G*01:01:08 genotypes frequency are higher among controls in comparison to patients (P value=0.028 and 0.007 respectively). The polymorphisms in HLA-G could affect GAC induction and its outcome. Also, increased sHLA-G levels in serum might be a useful biomarker for diagnosis.

Ostapchuk EO, Perfi L'eva YV, Talaeva ShZh, et al.
Content of HLA-G(+) T Cells in the Peripheral Blood from Healthy Women and Breast Cancer Patients.
Bull Exp Biol Med. 2015; 159(5):649-51 [PubMed] Related Publications
The number of CD3(+)CD56-HLA-G(+) cells in the peripheral blood of breast cancer patients was shown to increase by 2 times. Our results and published data suggest that the increase in the relative content of CD3(+)CD56-HLA-G(+) cells in the circulating blood in breast cancer contributes to tumor development due to suppression of antitumor immunity.

Bian X, Si Y, Zhang M, et al.
Down-expression of miR-152 lead to impaired anti-tumor effect of NK via upregulation of HLA-G.
Tumour Biol. 2016; 37(3):3749-56 [PubMed] Related Publications
It is known that chronic HBV infection (CHB) is the major risk factor for hepatocellular carcinoma (HCC) because CHB could not only cause liver tumorigenesis but also lead to change of local microenviroment and lower immune response to infected and cancerous cells (immune tolerance). Human leucocyte antigen-G (HLA-G) belongs to a non-classic MHC-I family and was considered to be an immune tolerance molecule, which could bind to immunosuppressive receptors of natural killer cell (NK) and T cells and trigger immunosuppressive signaling. Recently, numerous studies highlighted that microRNAs (miRNAs) were significantly differentially expressed in HCC tumorigenesis, and the expression was tissue-specific, indicating that miRNAs may cause great epigenetic changes in HCC tumorigenesis. In this study, we found that the expression of HLA-G was upregulated by hepatitis B virus (HBV) infection and miR-152; a HLA-G-targeting miRNA was downregulated by HBV infection. And high expression of HLA-G further suppressed NK against cancer cells, providing a new concept that miR-152 was involved in HBV-induced hepatocellular carcinoma.

Wu D, Kuiaste I, Moreau P, et al.
Rescuing lymphocytes from HLA-G immunosuppressive effects mediated by the tumor microenvironment.
Oncotarget. 2015; 6(35):37385-97 [PubMed] Free Access to Full Article Related Publications
Several studies have demonstrated that the antitumor activities of both T and natural killer (NK) effector populations are limited by the immunosuppressive strategies of tumors. In several malignant transformations, the expression of HLA-G by tumor cells rises dramatically, rendering them strongly immunosuppressive. In this study, we postulated that the absence of HLA-G receptors would prevent the immunosuppressive effects of both soluble and membrane-bound HLA-G. Thus, we investigated the therapeutic potential of effector NK cells genetically modified to downregulate the expression of ILT2 (HLA-G receptor) on their cell surfaces. We have shown that the proliferation of modified NK is still dependent on stimulation signals (no malignant transformation). ILT2- NK cells proliferate, migrate, and eliminate HLA-G negative targets cells to the same extent parental NK cells do. However, in the presence of HLA-G positive tumors, ILT2- NK cells exhibit superior proliferation, conjugate formation, degranulation, and killing activities compared to parent NK cells. We tested the effectiveness of ILT2- NK cells in vivo using a xenograft cancer model and found that silencing ILT2 rescued their anti-tumor activity.We believe that combining ILT2- NK cells with existing therapeutic strategies will strengthen the antitumor response in cancer patients.

Haghi M, Hosseinpour Feizi MA, Sadeghizadeh M, Lotfi AS
14-bp Insertion/Deletion Polymorphism of the HLA-G gene in Breast Cancer among Women from North Western Iran.
Asian Pac J Cancer Prev. 2015; 16(14):6155-8 [PubMed] Related Publications
BACKGROUND: The human leukocyte antigen-G (HLA-G) gene is highly expressed in cancer pathologies and is one strategy used by tumor cells to escape immune surveillance. A 14-bp insertion/deletion (InDel) polymorphism of the HLA-G gene has been suggested to be associated with HLA-G mRNA stability and the expression of HLA-G. The aim of present study was to assess any genetic association between this polymorphism and breast cancer among Iranian-Azeri women.
MATERIALS AND METHODS: In this study 227 women affected with breast cancer, in addition to 255 age-sex and ethnically matched healthy individuals as the control group, participated. Genotyping was performed using polymerase chain reaction and electrophoresis assays. The data were compiled according to the genotype and allele frequencies, compared using the Chi-square test. Statistical significance was set at P<0.05.
RESULTS: In this case-control study, no significant difference was found between the case and control groups at allelic and genotype levels, although there is a slightly higher allele frequency of HLA-G 14bp deletion in breast cancer affected group. However,when the stage I subgroup was compared with stage II plus stage III subgroup of affected breast cancer, a significant difference was seen with the 14 bp deletion allele frequency. The stage II-III subgroup patients had higher frequency of deletion allele (57.4% vs 45.8%) than stage I cases (χ2=4.16, p-value=0.041).
CONCLUSIONS: Our data support a possible action of HLA-G 14bp InDel polymorphism as a potential genetic risk factor for progression of breast cancer. This finding highlights the necessity of future studies of this gene to establish the exact role of HLA-G in progression steps of breast cancer.

Song B, Guan Z, Liu F, et al.
Long non-coding RNA HOTAIR promotes HLA-G expression via inhibiting miR-152 in gastric cancer cells.
Biochem Biophys Res Commun. 2015; 464(3):807-13 [PubMed] Related Publications
Recent studies have shown that the long non-coding RNA HOTAIR plays critical roles in tumor biology, including cancer progression and metastasis. However, the potential biological role HOTAIR in tumor escape remains undefined. Here, HOTAIR expression was measured in sixty paired gastric cancer (GC) tissue samples by real-time PCR, and then subjected to correlation analysis with human leukocyte antigen (HLA)-G levels which show close links with tumor escape mechanisms. Significant HOTAIR overexpression was observed in GC tissues, as well as strong positive correlations with HLA-G levels in both tissue and peripheral blood samples, detected by real-time PCR and ELISA assays respectively. Further gain- and loss-of-function studies indicated that HLA-G could be upregulated HOTAIR at both mRNA and secretion levels in vitro. On the other hand, bioinformatics analysis indicated the interaction between HOTAIR and miR-152, which shows potential regulation on HLA-G. And, altered miR-152 expression in GC tissues was also identified, and showed negative correlation with HOTAIR expression. Moreover, the negative regulation of miR-152 on HLA-G was verified in GC cells, while miR-152 induced decrease of HLA-G 3'UTR activity could be attenuated by HOTAIR co-overexpression with the assistant of mutation studies. Therefore, it was concluded that HOTAIR overexpression might also get involved in tumor escape mechanisms, involving HLA-G upregulation via inhibiting miR-152. Furthermore, this study recommended the potential application of HOTAIR in GC immunotherapy for better prognosis and improved survival.

Alves BM, Prellwitz IM, Siqueira JD, et al.
The effect of human leukocyte antigen G alleles on human papillomavirus infection and persistence in a cohort of HIV-positive pregnant women from Brazil.
Infect Genet Evol. 2015; 34:339-43 [PubMed] Related Publications
Patients with compromised immune systems have more severe intraepithelial lesions and more rapid disease progression, in addition to increased risk for cervical cancer. Persistent infection by the human papillomavirus (HPV) is a necessary step in that process. By inducing expression of inhibitory ligands of natural killer cells, like HLA-G, HPV avoids the elimination of infected cells. Recent studies have investigated polymorphisms in HLA-G that may be associated with susceptibility to HPV infection and persistence. One hundred-forty HIV(+) pregnant women from Brazil had a DNA fragment comprising HLA-G exons 2-4 PCR-amplified, cloned, sequenced and analyzed for allele determination. Altogether, 22 alleles comprising 52 different genotypes were found. Four novel HLA-G alleles were characterized. We have not observed association of specific HLA-G alleles with HPV infection, but found a protective effect of the G:01:01:02 allele against the occurrence of intraepithelial lesions. In addition to describing new HLA-G alleles and defining new reference sequences, our data provide a better understanding of the impact of HLA-G alleles on HPV-related disease.

Wang Y, Fan X, Li H, et al.
Tumor border sharpness correlates with HLA-G expression in low-grade gliomas.
J Neuroimmunol. 2015; 282:1-6 [PubMed] Related Publications
Human leukocyte antigen-G (HLA-G) is a tumor microenvironment molecule that is involved in the escape of cancerous tumors from host immune recognition and destruction. This study investigated the potential relationship between HLA-G expression levels and the sharpness of low-grade glioma tumor borders in magnetic resonance images. Preoperative T2-weighted images from 72 patients were retrospectively examined by manually segmenting the hyperintensive tumor areas and subsequently registering them to a standard brain template. Then, the intensity of the voxels inside the tumor border (tumor voxels) was compared with that of the voxels outside the tumor border (paratumor voxels). The radiologic sharpness of a tumor was defined as the mean ratio of the intensity of the tumor voxels to the intensity of the paratumor voxels. Tumors with high HLA-G expression were associated with larger tumors and lower mean hyperintensive contrast. These findings suggest that tumors with blurred boundaries may be those prone to diffuse invasion. Additionally, patients with tumors having high HLA-G expression were less likely to have undergone complete resections. Thus, this study is the first to identify an association between HLA-G expression and the radiologic morphology of the tumor border, and may further our understanding of the role of the HLA gene in immune escape in patients with low-grade gliomas.

Yang Y, Adachi K, Sheridan MA, et al.
Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure.
Proc Natl Acad Sci U S A. 2015; 112(18):E2337-46 [PubMed] Free Access to Full Article Related Publications
Human pluripotent stem cells (PSCs) show epiblast-type pluripotency that is maintained with ACTIVIN/FGF2 signaling. Here, we report the acquisition of a unique stem cell phenotype by both human ES cells (hESCs) and induced pluripotent stem cells (iPSCs) in response to transient (24-36 h) exposure to bone morphogenetic protein 4 (BMP4) plus inhibitors of ACTIVIN signaling (A83-01) and FGF2 (PD173074), followed by trypsin dissociation and recovery of colonies capable of growing on a gelatin substratum in standard medium for human PSCs at low but not high FGF2 concentrations. The self-renewing cell lines stain weakly for CDX2 and strongly for NANOG, can be propagated clonally on either Matrigel or gelatin, and are morphologically distinct from human PSC progenitors on either substratum but still meet standard in vitro criteria for pluripotency. They form well-differentiated teratomas in immune-compromised mice that secrete human chorionic gonadotropin (hCG) into the host mouse and include small areas of trophoblast-like cells. The cells have a distinct transcriptome profile from the human PSCs from which they were derived (including higher expression of NANOG, LEFTY1, and LEFTY2). In nonconditioned medium lacking FGF2, the colonies spontaneously differentiated along multiple lineages, including trophoblast. They responded to PD173074 in the absence of both FGF2 and BMP4 by conversion to trophoblast, and especially syncytiotrophoblast, whereas an A83-01/PD173074 combination favored increased expression of HLA-G, a marker of extravillous trophoblast. Together, these data suggest that the cell lines exhibit totipotent potential and that BMP4 can prime human PSCs to a self-renewing alternative state permissive for trophoblast development. The results may have implications for regulation of lineage decisions in the early embryo.

Wiśniewski A, Kowal A, Wyrodek E, et al.
Genetic polymorphisms and expression of HLA-G and its receptors, KIR2DL4 and LILRB1, in non-small cell lung cancer.
Tissue Antigens. 2015; 85(6):466-75 [PubMed] Related Publications
Human leukocyte antigen-G (HLA-G) is a nonclassical HLA class I molecule absent from most normal tissues but detected in many malignant tumors. It is recognized by cells of the immune system using LILRB1, KIR2DL4 and LILRB2 receptors. We attempted to find out whether some polymorphisms of HLA-G, LILRB1 and KIR2DL4 genes are associated with susceptibility to nonsmall cell lung cancer (NSCLC). Four polymorphisms in HLA-G, i.e. -964A>G (rs1632947), -725C>G>T (rs1233334), -716T>G (rs2249863) in the promoter, and a 14 base pair insertion/deletion (14 bp indel) in the 3'-untranslated region (3'UTR), and five in LILRB1 - 5651G>A (rs41308748) in intron 14, 5717C>T L622L (rs1061684), 5724G>A E625K (rs16985478), 5774 C>A P641P (rs41548213) in exon 15, and 5806C>T (rs8101240) in 3'UTR - as well as 9620 9A/10A (rs11410751) polymorphism in exon 7 of KIR2DL4 were typed using different laboratory techniques. Only one single nucleotide polymorphism (SNP) in HLA-G (-964A>G) and one in LILRB1 (5724G>A) were found to influence the risk of NSCLC. In addition, 5724G>A was associated with protection from tumor cell infiltration of regional lymph nodes. Most importantly, we detected HLA-G and LILRB1 expression in tumor specimens, but no correlation with genetic polymorphisms was observed. HLA-G and LILRB1 protein expression levels in tumor tissue were significantly correlated with tumor stage.

Amiot L, Vu N, Samson M
Biology of the immunomodulatory molecule HLA-G in human liver diseases.
J Hepatol. 2015; 62(6):1430-7 [PubMed] Related Publications
The non-classical human leukocyte antigen-G (HLA-G), plays an important role in inducing tolerance, through its immunosuppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. It would therefore appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression. The generation of immune tolerance is a role common to both HLA-G, as a molecule, and the liver, as an organ. This review provides a summary of the evidence implicating HLA-G in liver diseases. In the normal liver, HLA-G transcripts can be detected, but there is no HLA-G protein. However, HLA-G protein is detectable in the liver tissues and/or plasma of patients suffering from hepatocellular carcinoma, hepatitis B or C, or visceral leishmaniasis and in liver transplant recipients. The cells responsible for producing HLA-G differ between diseases. HLA-G expression is probably induced by microenvironmental factors, such as cytokines. The expression of HLA-G receptors, such as ILT2, ILT4, and KIRD2L4, on liver cells has yet to be investigated, but these receptors have been detected on all types of immune cells, and such cells are present in liver. The tolerogenic properties of HLA-G explain its deleterious effects in cancers and its beneficial effects in transplantation. Given the key role of HLA-G in immune tolerance, new therapeutic agents targeting HLA-G could be tested for the treatment of these diseases in the future.

Fock V, Plessl K, Fuchs R, et al.
Trophoblast subtype-specific EGFR/ERBB4 expression correlates with cell cycle progression and hyperplasia in complete hydatidiform moles.
Hum Reprod. 2015; 30(4):789-99 [PubMed] Related Publications
STUDY QUESTION: Do trophoblast subtypes differ in their expression of erythroblastic leukaemia viral oncogene homologue (ERBB) receptor family members and responsiveness towards specific growth factor ligands?
SUMMARY ANSWER: Our data reveal a reciprocal expression pattern of epidermal growth factor receptor (EGFR)/ERBB4 in proliferative and ERBB2/ERBB3 in invasive trophoblast subtypes, as well as a restricted responsiveness to epidermal growth factor (EGF) and heparin-binding (HB)-EGF.
WHAT IS KNOWN ALREADY: EGFR is expressed by villous cytotrophoblasts (vCTBs), but absent from extravillous trophoblasts (EVTs), which specifically up-regulate ERBB2.
STUDY DESIGN, SIZE, DURATION: Tissue samples of human first trimester placentae (n = 50) and deciduae (n = 5) obtained from elective pregnancy terminations were used to study trophoblast subtype-specific ERBB receptor expression and responsiveness to recombinant human EGF and HB-EGF. Age-matched complete hydatidiform mole (CHM) placentae (n = 12) were assessed for EGFR and ERBB4 expression in proliferation-competent regions.
PARTICIPANTS/MATERIALS, SETTING, METHODS: ERBB receptor expression was analysed in primary trophoblast cell isolates by means of microarray, quantitative real-time PCR and western blotting, as well as immunofluorescence stainings of placental and decidual tissue sections. EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR(+) and HLA-G(+) trophoblasts. 5-Ethynyl-2'-deoxyuridine incorporation assays were performed to study the effect of both ligands on the proliferative capacity of primary trophoblasts as well as of vCTBs and proximal cell column trophoblasts (pCCTs) in placental floating explants. Finally, the average number of EGFR(+) vCTB and pCCT layers was determined in CHM placentae and compared with healthy age-matched controls.
MAIN RESULTS AND THE ROLE OF CHANCE: Proliferative vCTBs and pCCTs co-express EGFR and ERBB4, but are devoid of ERBB2 and ERBB3. In contrast, HLA-G(+) trophoblast subtypes exhibit an EGFR/ERBB4(-) and ERBB2/ERBB3(+) phenotype. EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal-regulated kinase 1/2 in EGFR(+) primary trophoblasts; however, they do not show an effect on HLA-G(+) EVTs. Both ligands strongly induce cell cycle progression in primary trophoblasts (P < 0.05) and placental explant-associated vCTBs (P < 0.05) and pCCTs (P < 0.05). Notably, EGFR(+) vCTB (P < 0.0001) and pCCT (P < 0.0001) layers are significantly expanded in CHM placentae when compared with healthy controls.
LIMITATIONS, REASONS FOR CAUTION: Cells were removed from their physiological context and may therefore respond differently to various stimuli.
WIDER IMPLICATIONS OF THE FINDINGS: In this study we define EGFR as a marker for proliferative trophoblast subtypes within the human placenta. Manipulation of EGFR signalling might thus offer a promising therapeutic avenue for the treatment of molar pregnancies associated with trophoblast hyperplasia.
STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P.). There are no competing interests to declare.

Ueshima C, Kataoka TR, Hirata M, et al.
The Killer Cell Ig-like Receptor 2DL4 Expression in Human Mast Cells and Its Potential Role in Breast Cancer Invasion.
Cancer Immunol Res. 2015; 3(8):871-80 [PubMed] Related Publications
The killer-cell Ig-like receptor (KIR) 2DL4 (CD158d) acts as a receptor for human leukocyte antigen (HLA)-G and is expressed on almost all human natural killer (NK) cells. The expression and function of KIR2DL4 in other hematopoietic cells is poorly understood. Here, we focused on human mast cells, which exhibit cytotoxic activity similar to that of NK cells. KIR2DL4 was detected in all examined human cultured mast cells established from peripheral blood derived from healthy volunteers (PB-mast), the human mast cell line LAD2, and human nonneoplastic mast cells, including those on pathologic specimens. An agonistic antibody against KIR2DL4 decreased KIT-mediated and IgE-triggered responses, and enhanced the granzyme B production by PB-mast and LAD2 cells, by activating Src homology 2-containing protein tyrosine phosphatase (SHP-2). Next, we performed a coculture assay between LAD2 cells and the HLA-G(+) cancer cells, MCF-7 and JEG-3, and showed that KIR2DL4 on LAD2 cells enhanced MMP-9 production and the invasive activity of both cell lines via HLA-G. Immunohistochemical analysis revealed that the direct interaction between HLA-G(+) breast cancer cells and KIR2DL4(+) tissue mast cells (observed in 12 of 36 cases; 33.3%) was statistically correlated with the presence of lymph node metastasis or lymph-vascular invasion (observed in 11 of 12 cases; 91.7%; χ(2) = 7.439; P < 0.01; degrees of freedom, 1) in the clinical samples. These findings suggest that the KIR2DL4 on human mast cells facilitates HLA-G-expressing cancer invasion and the subsequent metastasis.

Bielska M, Bojo M, Klimkiewicz-Wojciechowska G, et al.
Human leukocyte antigen-G polymorphisms influence the clinical outcome in diffuse large B-cell lymphoma.
Genes Chromosomes Cancer. 2015; 54(3):185-93 [PubMed] Related Publications
The role of HLA-G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T, and HLA-G 14-base pair, have any influence on the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G-725GG or the HLA-G-725GC genotype were lower, and those of the HLA-G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA-G-725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (P = 0.003). The homozygous HLA-G del/del had a lower probability of OS than subjects carrying the HLA-G deletion/insertion (del/ins) or the HLA-G ins/ins genotype (P = 0.009). Two HLA-G genotype-based risk groups were defined according to the genotype distribution. The high-risk (HR) group presented a shorter OS than low-risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI-risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA-G polymorphisms for the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibility to DLBCL thus deserves further study.

Li T, Huang H, Liao D, et al.
Genetic polymorphism in HLA-G 3'UTR 14-bp ins/del and risk of cancer: a meta-analysis of case-control study.
Mol Genet Genomics. 2015; 290(4):1235-45 [PubMed] Related Publications
Accumulating evidence has suggested that the human leucocyte antigen-G (HLA-G) 14 bp ins/del polymorphism might be related to cancer susceptibility. However, epidemiologic findings have been inconsistent. Therefore, we performed a meta-analysis of case-control study to derive a more precise estimation of this association. Electronic databases were searched to identify all eligible studies of HLA-G 14 bp ins/del polymorphism and cancer risk. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to evaluate the strength of the association in fixed-effects model or random-effects model according to heterogeneity. Publication bias, sensitivity analysis and subgroup analyses based on cancer type, ethnicity, source of controls and sample size were also performed. A total of 14 case-control studies, involving 2,757 cases and 3,972 controls, were included in the present meta-analysis. The pooled analysis showed that there is no significant relationship between the HLA-G 14 bp ins/del polymorphism and cancer susceptibility under the genetic models (for the allele model del vs. ins: OR 1.13, 95 % CI 1.00-1.27; for the homozygote comparison model del/del vs. ins/ins: OR 1.22, 95 % CI 0.95-1.56; for the dominant model del/del + ins/del vs. ins/ins: OR 1.15, 95 % CI 0.94-1.42; for recessive model del/del vs. ins/del + ins/ins: OR 1.13, 95 % CI 0.96-1.34; respectively). Subgroup analyses indicated significant association among breast cancer, population based control and the large sample size group in some genetic models. Our investigations demonstrate that genotypes for the HLA-G 14 bp ins/del polymorphism may be not associated with overall cancer risk. In a subgroup meta-analysis, however, HLA-G 14-bp ins/del polymorphism might contribute to breast cancer susceptibility.

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