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Several genes have been associated with breast cancer (BC) susceptibility. The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and interferon lambda receptor 1 (IFNLR1) genes encode receptors that mediate the action of inflammatory cytokines. Previous studies have demonstrated the association of the variants rs1800693 (TNFRSF1A) and rs4649203 (IFNLR1) with some inflammatory diseases. The present study aimed to verify a possible association of these variants with BC, its clinical pathologic features, as well as epidemiological data in a Brazilian population. A total of 243 patients and 294 individuals without history of BC were genotyped for these polymorphisms through TaqMan® SNP genotyping assays by qPCR. For the TNFRSF1A gene, no significant results were found. For IFNLR1, the AA genotype (p = 0.008) and the A allele (p = 0.02) were significantly associated with a lower risk of developing BC. When analyzing the age, it was observed that each increase of one year contributes to the development of BC (p

Made available in DSpace on 2018-12-11T17:22:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-10-01 Background: HLA-G is an immune checkpoint molecule. Since a differential molecule expression has been reported even for healthy individuals, many studies have focused on polymorphisms at HLA-G regulatory regions, particularly the 3′ untranslated region (3′UTR). The presence/absence of a 14-bp sequence was the first polymorphism described and it is the most studied in association between HLA-G and disorders. Methods: In this study, we performed a systematic review and meta-analysis of all association studies published regarding the HLA-G 14-bp. Results: We verified association between 14-bp alleles and diseases in the following situations: (1) presence of 14-bp (insertion) conferred susceptibility to preeclampsia (child alleles evaluated) and systemic lupus erythematosus (OR = 1.42; 95%CI = 1.04–1.93; p = 0.026 and OR = 1.13; 95%CI = 1.01–1.27, p = 0.028); (2) 14-bp absence (deletion) was associated with increased risk to breast cancer (OR = 1.23; 95%CI = 1.06–1.43; p = 0.006) and human Cytomegalovirus infection (OR = 2.06; 95%CI = 1.60–2.64; p < 0.0001); and (3) a risk association was observed between the group of reproductive disorders and the 14-bp insertion (OR = 1.12; 95%CI = 1.01–1.24; p = 0.034). Conclusions: Considering that others 14-bp associations were inconclusive and that other variation sites observed at HLA-G 3′UTR exhibit a proven role on post-transcriptional regulation of HLA-G expression, the complete 3′UTR segment should be analyzed in terms of disease susceptibility, instead of a single polymorphism. Divisão de Imunologia Clínica Departamento de Clínica Médica Faculdade de Medicina de Ribeirão Preto (FMRP) Universidade de São Paulo (USP) Laboratório Multiusuário de Estudos em Biologia Centro de Ciências Biológicas Universidade Federal de Santa Catarina (UFSC) Departamento de Biologia Celular Embriologia e Genética Centro de Ciências Biológicas Universidade Federal de Santa Catarina (UFSC) Departamento de Patologia Faculdade de Medicina de Botucatu Unesp – Univ. Estadual Paulista Faculdade de Filosofia Ciências e Letras de Ribeirão Preto (FFCLRP) Universidade de São Paulo (USP) Departamento de Patologia Faculdade de Medicina de Botucatu Unesp – Univ. Estadual Paulista

// Layale Yaghi 1, 2, 3 , Isabelle Poras 1, 2 , Renata T. Simoes 1, 2, 4 , Eduardo A. Donadi 5 , Jorg Tost 6, 7 , Antoine Daunay 6 , Bibiana Sgorla de Almeida 1, 2, 5 , Edgardo D. Carosella 1, 2 , Philippe Moreau 1, 2 1 Commissariat a l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Therapies Innovantes, Service de Recherches en Hemato-Immunologie, Hopital Saint-Louis, Paris, France 2 Universite Paris-Diderot, Sorbonne Paris-Cite, UMR E5, Institut Universitaire d’Hematologie, Hopital Saint-Louis, Paris, France 3 Lebanese University, School of Medicine, Hadath, Lebanon 4 Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, IEP/SCBH, Belo Horizonte, Minas Gerais, Brasil 5 Divisao de Imunologia Clinica, Departamento de Clinica Medica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brasil 6 Centre d’Etude du Polymorphisme Humain, Fondation Jean-Dausset, Laboratory for Functional Genomics, Paris, France 7 Commissariat a l’Energie Atomique et aux Energies Alternatives, Centre National de Genotypage, Laboratory for Epigenetics and Environment, Evry, France Correspondence to: Philippe Moreau, email: philippe.moreau@cea.fr Keywords: HLA-G, HIF-1, exon 2 HRE, glioma Received: July 02, 2016 Accepted: August 20, 2016 Published: August 26, 2016 ABSTRACT HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G . We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2’deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G . Both treatments enhanced the amount of HLA-G mRNA and protein in HLA-G negative U251MG glioma cells. Electrophoretic Mobility Shift Assays and luciferase reporter gene assays revealed that HLA-G upregulation depends on Hypoxia Inducible Factor-1 (HIF-1) and a hypoxia responsive element (HRE) located in exon 2. A polymorphic HRE at –966 bp in the 5’UT region may modulate the magnitude of the response mediated by the exon 2 HRE. We suggest that therapeutic strategies should take into account that HLA-G expression in response to hypoxic tumor environment is dependent on HLA-G gene polymorphism and DNA methylation state at the HLA-G locus.

Made available in DSpace on 2018-12-11T17:23:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-01-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5′ and 3′ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3′ untranslated region (3′UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3′UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3′UTR haplotypes in healthy individuals and reinforce that 3′UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G. Commissariat à l'Energie Atomique et aux Energies Alternatives Institut des Maladies Emergentes et des Thérapies Innovantes Service de Recherches en Hémato-Immunologie Hôpital Saint-Louis Université Paris-Diderot Sorbonne Paris-Cité UMR-E5 Institut Universitaire D'Hématologie Hôpital Saint-Louis Lebanese University School of Medicine Programa de Pósgraduação em Ciências da Saúde Centro de Ciências da Saúde Universidade Federal do Rio Grande do Norte Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo Departamento de Biologia Celular Embriologia e Genética Centro de Ciências Biológicas Universidade Federal de Santa Catarina Department of Genetics Ribeirão Preto Medical School University of São Paulo Divisão de Imunologia Clínica Departamento de Clínica Médica Faculdade de Medicina de Ribeirão Preto Universidade de São Paulo Department of Pathology School of Medicine Universidade Estadual Paulista Unesp Department of Pathology School of Medicine Universidade Estadual Paulista Unesp CAPES: 014747/2013-8 FAPESP: 2014/18730-9 CNPq: 406594/2013-9