Immunogenetics of prostate cancer and benign hyperplasia – the potential use of an HLA‐G variant as a tag SNP for prostate cancer risk

Abstract

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.

Genetic association between HLA-G 14-bp polymorphism and diseases: A systematic review and meta-analysis

“…Articles included comprised case-control studies involving the HLA-G 3′UTR 14-bp polymorphism and clinical situations/ diseases. Studies were grouped according to clinical characteristics, pathogenesis and immune response as follow: (1) cancer 2 -B-Cell Lymphoma [27], Breast Cancer [28][29][30][31][32], Cervical Cancer [33][34][35][36], Colorectal cancer [37], Esophageal Cancer [38], Hepatocellular Carcinoma [39][40][41], Head and Neck Squamous-Cell Carcinoma (HNSCC) [42], Lung Cancer [43], Neuroblastoma [44], Papillary Thyroid Cancer [45] and Prostate Cancer [46]; (2) autoimmune diseases 3 -Hashimoto's Thyroiditis [45], Juvenile Idiopathic Arthritis [47], Multiple Sclerosis [48][49][50][51], Non-segmental Vitiligo [52], Pemphigus Vulgaris [53], Rheumatoid Arthritis [47,[54][55][56][57][58], Systemic Lupus Erythematosus (LES) [59][60][61][62][63][64][65][66][67] and Type 1 Diabetes [68]…”

“…Chen et al, 2012 [37] appears two times in this group, because two different populations are described in the same article 3. Veit et al, 2008[46] appears two times in this group, because two distinct diseases data are described in the same article 4. García-González et al, 2014[69] andGlas et al, 2007 [77] appear two times in this group, because two distinct diseases data are described in each article 5.…”

Research Article Association of HLA-G 14-base pair insertion/deletion polymorphism with breast cancer in Saudi Arabia

“…The HLA-G molecule was reported for its tolerogenic function mainly in the maternal-fetal interface, helping to protect the fetus from destruction by the mother's immune defense system (Kovats et al, 1990;Menter and Tzankov, 2018;Galaviz-Hernandez et al, 2019). Considering the tolerogenic properties of the HLA-G molecule, many studies have detected an association between the aberrant expression of HLA-G and the occurrence of several types of malignancies such as colorectal cancer, esophageal cancer, uterine cervical cancer, ovarian carcinoma, hepatocellular carcinoma, carcinoma of bladder, and breast cancer (Rouas-Freiss et al, 2005a;Zidi and Ben Amor, 2011;Kim et al, 2013;Rolfsen et al, 2014;Rutten et al, 2014;Zhang and Tao Wang, 2014;Zidi et al, 2016;Zambra et al, 2016;de Almeida et al, 2018;Lin and Yan, 2018) as well as several other diseases such as infections, autoimmunity, and abortion (Donadi et al, 2011;Vargas et al, 2011;Garcia et al, 2013;Dias et al, 2015;Sabbagh et al, 2018;). Different polymorphisms located in coding and noncoding regions of the gene were reported to affect the biological activity of HLA-G. Polymorphism in the promoter or 3′-UTR influence HLA-G levels.…”

Co-infecção Plasmodium falciparum e Schistosoma haematobium: papel dos genes HLA não-clássicos de classe I (HLA-G, -E e -F) na suscetibilidade à malária

“…The HLA-G 3' UTR evaluated here revealed well-documented haplotypes (Tan et al 2005;Hviid et al 2006;Castelli et al 2010Castelli et al , 2011Castelli et al , 2014aCastelli et al , 2017Consiglio et al 2011;Lucena-Silva et al 2012Sizzano et al 2012;Veit et al 2012Veit et al , 2014Carlini et al 2013;Martelli-Palomino et al 2013;Santos et al 2013;Courtin et al 2013;Garcia et al 2013;Sabbagh et al 2014;Catamo et al 2014Catamo et al , 2015Garziera et al 2015;Gineau et al 2015;Porto et al 2015;Nilsson et al 2016;Zambra et al 2016;de Albuquerque et al 2016) (Table 8).…”

“…Up to date, approximately 14 variabe sites are frequently observed at the 3' UTR segment in worldwide populations, which are rearranged into several 3' UTR haplotypes, with UTR-01 to -07 the most frequent (minimum frequency of 4%) (Castelli et al 2010(Castelli et al , 2014a(Castelli et al , 2017Lucena-Silva et al 2012;Sabbagh et al 2014;de Albuquerque et al 2016;Nilsson et al 2016). Many studies conducted in several worldwide populations have evaluated HLA-G variability at the 5' upstream regulatory region (promoter), coding and/or 3' UTR segments (Tan et al 2005;Hviid et al 2006;Castelli et al 2010Castelli et al , 2011Consiglio et al 2011;Lucena-Silva et al 2012Sizzano et al 2012;Veit et al 2012Veit et al , 2014Carlini et al 2013;Martelli-Palomino et al 2013;Santos et al 2013;Courtin et al 2013;Garcia et al 2013;Sabbagh et al 2014;Catamo et al 2014Catamo et al , 2015Gineau et al 2015;Porto et al 2015;Garziera et al 2015;Nilsson et al 2016;Zambra et al 2016;de Albuquerque et al 2016). But, with the exception of a study reporting HLA-G variability based on the 1000 Genomes phase I data (Castelli et al 2014a), which is characterized by low depth of coverage, the complete HLA-G gene variability has not yet been characterized in African population samples.…”