Identification of the novel HLA-DRB3*03:69 allele by next-generation sequencing.

The new HLA-DRB3*03:69 allele differs from DRB3*03:01:01:03 by change of C → G in exon 3.

The novel HLA-DPA1*01:182 allele identified in a Brazilian bone marrow donor.

The new HLA-DPA1*01:182 allele differs from HLA-DPA1*01:03:01:04 by a single mismatch in exon 4.

The novel HLA-A*68:190:02 allele identified in a Brazilian bone marrow donor.

HLA-A*68:190:02 differs from A*68:190:01 by a single synonymous nucleotide change in exon 2.

Genetic Polymorphisms of the TGFB1 Signal Peptide and Promoter Region: Role in Wilms Tumor Susceptibility?

The aim of the present study was to investigate the rs1800468 (G-800A), rs1800469 (C-509T), rs1800470 (C29T), and rs1800471 (G74C) TGFB1 genetic polymorphisms and their haplotype structures in patients with Wilms Tumor (WT) and neoplasia-free controls. The genomic DNA was extracted from 35 WT patients and 160 neoplasia-free children, and the TGFB1 polymorphisms were genotyped by polymerase chain reaction, followed by restriction fragment length polymorphism. The haplotype structures were inferred, and permutation and logistic regression tests were performed to check for differences in haplotype distribution between the control and WT individuals. Positive associations were found in the recessive model for rs1800469 T allele (OR: 8.417; 95% CI: 3.177 to 22.297; P < 0.001) and for the rs1800470 C allele (OR: 3.000; 95% CI: 1.296 to 6.944; P = 0.01). Haplotype analysis revealed a significant negative association between GCTG and WT (OR: 0.236, 95% CI: 0.105 to 0.534; P = 0.0002); by contrast, the GTTG haplotype was associated with increased risk for WT (OR: 12.0; 95% CI: 4.202 to 34.270; P < 0.001). Furthermore, rs1800469 was negatively correlated with tumor size and a trend toward a positive correlation for capsular invasion was observed in the dominant model (Tau-b: -0.43, P = 0.02 and tau-b: 0.5, P = 0.06, respectively). This is the first study with rs1800468, rs1800469, rs1800470, and rs1800471 TGFB1 polymorphisms in WT, and our results suggest that the TGFB1 promoter and signal peptide region polymorphisms may be associated with WT susceptibility and clinical presentation.

Transforming growth factor beta 1 (TGFß1) plasmatic levels in breast cancer and neoplasia-free women: Association with patients' characteristics and TGFB1 haplotypes.

Transforming growth factor beta 1 (TGFß1) is a pleiotropic cytokine that acts in a context-dependent manner. In breast cancer (BC) this cytokine exerts subtype- and stage-specific roles, inhibiting poorly aggressive tumors while enhances the invasive potential of highly aggressive cancers. Single-nucleotide polymorphisms (SNPs) affecting TGFß1 production largely reflect this pattern of association, but studies investigating systemic TGFß1 levels in BC patients and their association with clinical features or SNPs produced conflicting conclusions. Therefore, the present work investigated plasmatic TGFß1 levels through enzyme linked immunosorbent assay (ELISA) in 341 individuals previously genotyped for four TGFB1 SNPs [G-800A (rs1800468), C-509T (rs1800469), T29C (rs1800470) and G74C (rs1800471)], encompassing 184 neoplasia-free women with clinical information regarding health status, 113 treatment-free pre-surgery BC patients and 44 treated BC patients. Results have shown that TGFß1 levels varied greatly in function of health status in neoplasia-free women, and disease-free individuals had higher TGFß1 levels than both treatment-free or treated BC patients. There was no correlation between TGFß1 with clinicopathological features in treatment-free BC general group, but it was negatively correlated with tumor size in luminal-B-HER2+ patients and with histopathological grade in triple-negative group. Also, TGFB1 ACTG haplotype (from G-800A to G74C) was associated with decreased TGFß1 levels compared to the reference GCTG haplotype, and regression analyses showed that this association was independent of age, health status or BC diagnosis. In conclusion, several factors may influence TGFß1 levels, and ACTG haplotype seems to be an important factor regulating TGFß1 production.

CXCL12 chemokine and CXCR4 receptor: association with susceptibility and prognostic markers in triple negative breast cancer.

CXCL12/CXCR4 signaling has been implicated in breast carcinogenesis, and genetic polymorphisms in these molecules have been associated with different types of cancer. The present study analyzed genetic polymorphisms in CXCL12 (rs1801157, G > A) and CXCR4 (rs2228014, C > T) and CXCR4 immunostaining in tumor tissues from patients with triple negative breast cancer (TNBC) aiming to evaluate their possible role in its' susceptibility and prognosis. Genetic polymorphisms were analyzed in 59 TNBC patients and 150 control women; age-adjusted logistic regression showed no association when variants were considered in isolation; however, a statistically significant interaction was noted for heterozygosis for both allelic variants increasing the odds for TNBC (CXCL12-GA by CXCR4-CT: OR 7.23; 95% CI 1.15-45.41; p = 0.035). CXCL12 polymorphism was correlated negatively with proliferation index (Ki67) (Tau-b = - 0.406; p = 0.006). CXCR4 immunostaining was evaluated in 37 TNBC patients (22 with paired tumor-normal adjacent tissue). CXCR4 was detected more intensely in cell cytoplasm than in membrane, and was more expressed in tumor than in normal adjacent tissues, although not statistically significant. CXCR4 expression on the membrane of tumor cells was correlated positively with histopathological grade (Tau-b = 0.271; p = 0.036) and negatively with lymph node metastasis (Tau-b = - 0.478; p = 0.036). The present study indicates that CXCL12 and CXCR4 polymorphisms and CXCR4 immunostaining might have susceptibility and prognostic roles in TNBC pathogenesis.

Transforming growth factor beta 1 (TGFß1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis.

PURPOSE: Despite the documented dual role of TGFß1 in breast cancer (BC) pathogenesis, the subtype-specific influences of its polymorphisms remain undocumented. The present study investigated the effects of the TGFB1 promoter region (rs1800468 or G-800A and rs1800469 or C-509T) and signal peptide (rs1800470 or C29T and rs1800471 or G74C) single nucleotide polymorphisms (SNPs) and their haplotype structures on the susceptibility and clinicopathological presentation of BC subtypes. METHODS: TGFB1 genotypes were assessed by PCR-RFLP and haplotype structures were inferred for 323 BC patients and 405 neoplasia-free women, and case-control analyses were performed by logistic regression adjusted by age. Clinicopathological parameters (age at diagnosis, tumor size, histopathological grade, lymph node metastasis, proliferation index and disease stage) were tested for correlation with TGFB1 variants. All statistical analyses were two-tailed with an alpha level of 0.05. RESULTS: Variants related to increased TGFß1 production (C-509T SNP and GTCG haplotype) were associated with increased susceptibility to HER2+ tumors and correlated with worse prognostic parameters in HER2+ and triple-negative (TN) BCs, but correlated negatively to Ki67 in ER/PR+HER2- tumors. Conversely, low TGFß1 production variants (C29T SNP and GCTG haplotype) were protective against HER2+ tumors and correlated negatively with prognostic parameters in HER2+ and TN BCs, while indicating higher proliferation rates in ER/PR+HER2- tumors. Furthermore, the GCCG haplotype was associated with decreased susceptibility to ER/PR+HER2- tumors, but correlated positively with Ki67 in this subgroup. CONCLUSION: The present study indicates that TGFB1 variants have subtype-specific roles in BC and may switch from tumor suppressor to promoter during tumor development, consistent with TGFß1 dual role in BC pathogenesis.

Genetic Polymorphism in the Promoter Region of Serotonin Transporter: Implications for Ethanol Abuse in Children and Adolescents.

OBJECTIVES: To provide a review of published literature regarding genetic polymorphism of serotonin transporter gene, named as 5-HTTLPR, and its potential role as a susceptibility marker for ethanol abuse in childhood and adolescence. METHODS: A literature review of several databases was conducted with the following keywords: 5-HTTLPR, children or adolescents or teenagers, susceptibility, alcohol or ethanol, abuse or misuse. RESULTS: Alcohol interacts with serotonergic synaptic transmission in several ways, and the reduced availability of serotonin transporters might foster brain dysfunction, driving to alcohol abuse. The initial use of ethanol in children and adolescents is determined primarily by environmental influences, whereas the establishment of drinking patterns is strongly controlled by genetic factors. Functional polymorphic variants in the promoter region of the 5-HTTLPR gene have age-dependent effects in alcohol abuse. This polymorphism, mapped to the 5' region of the SLC6A4, is a variable number of tandem repeats (VNTR) and involves a direct repeat of 20-23 base pairs GC-rich sequences, comprising a short (S) allele, consisting of 14 repeats, and a long (L) allele, with 16 repeats. Additional variants have been described, although their influences on childhood and adolescence ethanol use are not clear. CONCLUSION: The influence of the 5-HTTLPR allelic variants in children and adolescent misuse of alcohol might be considered for clinical management, preventing long-term behavior problem. Identifying genetic markers associated to the potential alcohol misuse or abuse could be useful in guiding management and formulating effective coping strategies.

OBJECTIFS: Offrir une revue de la littérature publiée sur le polymorphisme génétique du gène transporteur de la sérotonine, nommé 5-HTTLPR, et son rôle potentiel de marqueur de la susceptibilité à l'abus d'éthanol dans l'enfance et l'adolescence. MÉTHODES: Une revue de la littérature dans plusieurs bases de données a été menée à l'aide des mots clés suivants: 5-HTTLPR, enfants ou adolescents ou teenagers, susceptibilité, alcool ou éthanol, abus ou excès. RÉSULTATS: L'alcool interagit de plusieurs façons avec la transmission synaptique sérotoninergique, et la disponibilité réduite des transporteurs de la sérotonine peut favoriser une dysfonction cérébrale, qui mène à l'abus d'alcool. L'utilisation initiale d'éthanol chez les enfants et les adolescents est déterminée principalement par des influences environnementales, alors que l'établissement de modèles de consommation d'alcool est fortement contrôlé par des facteurs génétiques. Les variantes polymorphiques fonctionnelles de la région promotrice du gène 5-HTTLPR ont des effets selon l'âge sur l'abus d'alcool. Ce polymorphisme, localisé à la région 5' de SLC6A4, est un nombre variable de répétitions en tandem (NVRT) et implique une répétition directe de séquences de 20­23 paires de base riches en GC, comprenant un allèle court (C), consistant en 14 répétitions, et un allèle long (L), avec 16 répétitions. Les variantes additionnelles ont été décrites, bien que leurs influences sur l'utilisation d'éthanol dans l'enfance et l'adolescence ne soient pas définies. CONCLUSION: L'influence des variantes alléliques de 5-HTTLPR sur l'excès d'alcool chez les enfants et les adolescents pourrait être considérée pour la prise en charge clinique, et la prévention de problèmes de comportement à long terme, L'identification des marqueurs génétiques associés à l'excès ou l'abus d'alcool potentiel pourrait être utile pour guider la prise en charge et formuler des stratégies d'adaptation efficaces.

Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases.

The FOXP3 gene encodes a transcription factor thought to be important for the development and function of regulatory T cells (Treg cells). These cells are involved in the regulation of T cell activation and therefore are essential for normal immune homeostasis. Signals from microenvironment have a profound influence on the maintenance or progression of diseases. Thus, Tregs have an important marker protein, FOXP3, though it does not necessarily confer a Treg phenotype when expressed. FOXP3 polymorphisms that occur with high frequency in the general populations have been studied in common multifactorial human diseases. Dysfunction of FOXP3 gene product could result in lack of Treg cells and subsequently chronically activated CD4+ T cells which express increased levels of several activation markers and cytokines, resulting in some autoimmune diseases. In contrast, high Treg levels have been reported in peripheral blood, lymph nodes, and tumour specimens from patients with different types of cancer. The present study discusses the polymorphisms located in intron, exon and promoter regions of FOXP3 which have already been investigated by many researchers. FOXP3 has received considerable attention in attempts to understand the molecular aspect of Treg cells. Therefore, in the present study, the relationship between genetic polymorphism of FOXP3 in Treg-cell role and in disease development are reviewed considering the interactive effect of genetic factors.