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

Analysis of CXCL12 and CXCR4 genetic polymorphisms and CXCR4 protein expression in triple-negative breast cancer patients

O câncer de mama apresenta subtipos com diferentes aspectos histológicos, manifestações clínicas e variações de resposta ao tratamento. Dentre estes subtipos, os tumores triplo-negativos (TN) são responsáveis por 10-20% dos cânceres de mama e são muito agressivos. Caracterizam-se por possuir fenótipo de receptor de estrógeno (RE) e de progesterona (RP) negativos e fator de crescimento epidérmico humano 2 (HER2) negativo. No aspecto da imunologia, o eixo constituído pela C-X-C quimiocina 12 (CXCL12) e o receptor de C-X-C quimiocina 4 (CXCR4) parece desempenhar um importante papel na disseminação de tumores sólidos, incluindo o câncer de mama. O gene que codifica a quimiocina CXCL12 apresenta um polimorfismo (rs1801157) que pode ter funções regulatórias importantes pelo aumento na concentração da quimiocina. O gene que codifica para CXCR4 também apresenta uma mutação polimórfica (rs2228014) que pode aumentar a suscetibilidade ao câncer de mama e a indução de metástases. Dentro deste contexto, este trabalho teve como objetivos analisar estes polimorfismos em pacientes com câncer de mama TN e em controles livres de neoplasia, bem como a expressão protéica de CXCR4 em tecido tumoral e normal adjacente, na busca por marcadores para a carcinogênese mamária subtipo específica. Os polimorfismos foram avaliados em 59 pacientes e 150 controles pelo método de reação em cadeia da polimerase e polimorfismo do comprimento dos fragmentos de restrição (PCR-RFLP), seguido de eletroforese em gel de poliacrilamida e coloração com prata. A expressão do CXCR4 foi avaliada por imunohistoquímica (IHQ) em 37 amostras de tecido incluídos em parafina. A análise estatística foi realizada pelo cálculo da Odds ratio (OR) com intervalo de confiança de 95% (IC95%), e pelos testes do Qui-Quadrado de Pearson, exato de Fisher e Correlação de Spearman através do programa estatístico SPSS (versão 20.0). Os resultados indicaram ausência de associação significativa entre os polimorfismos rs1801157 no CXCL12 (homozigoto para o alelo variante: OR=2,63; IC95%=0,51-13,39 e portador do alelo variante: OR=1,58; IC95%=0,83-2,99) ers2228014no CXCR4 (portador do alelo variante: OR=1,89; IC95%=0,58-6,22) em relação ao câncer TN, mesmo quando foi realizada a análise combinada em ambos os genes de genótipos considerados de risco (OR=3,56; IC95%=0,77-16,44). Quando foram considerados os parâmetros prognósticos, os resultados também não foram significativos em relação ao tamanho de tumor (CXCL12: p=0,420; CXCR4: p=0,925), metástase em linfonodo (CXCL12: p=0,596; CXCR4: p=0,516) e grau histológico (CXCL12: p=0,192; CXCR4: p=0,070).A análise pela IHQ demonstrou que a expressão de CXCR4 é mais citoplasmática do que em nível de membrana e que este receptor se expressou tanto no tecido normal quanto no tumoral.Porém, sua expressão citoplasmática foi mais acentuada no tecido tumoral em relação ao tecido normal adjacente. Assim sendo, os genes CXCL12 e CXCR4 não se mostraram candidatos a marcadores de suscetibilidade para o câncer de mama TN, apesar dos resultados terem indicado uma tendência ao alelo variante estar mais presente no grupo das pacientes, especialmente quando ambos os polimorfismos foram considerados de forma simultânea. O fato de CXCR4 citoplasmático ter sido mais expresso no tecido tumoral em relação ao normal adjacente deve ser levado em consideração e reavaliado em amostras maiores de subtipos tumorais, pela importância prognóstica que pode representar.Breast cancer presents different histological subtypes with clinical manifestations and response to treatment variations. Among the subtypes, the triple-negative tumors (TN) account for 10-20%of breast cancers and are biologically very aggressive. The TN tumors are characterized by possessing negative estrogen receptor (ER) phenotype, negative progesterone receptor (PR) phenotype and negative overexpression of 2-human epidermal growth factor (HER2). In the aspect of immunology, the axis constituted by the C-X-C chemokine 12 (CXCL12) and the C-X-C receptor 4 (CXCR4) appears to play an important role in solid tumor dissemination, including the breast one. The gene encoding CXCL12 presents a polymorphism (rs1801157) that may have important regulatory functions as result of increased protein concentration. The gene encoding CXCR4 also has a polymorphic variation (rs2228014), which can increase breast cancer susceptibility and metastasis induction. Within this context, the present study aimed to analyze these polymorphisms on CXCL12 and CXCR4 in TN breast cancer patients and cancer-free controls, and to evaluate CXCR4 protein expression in tumor and adjacent normal tissues, in a search for susceptibility and prognostic markers for specific subtype of breast carcinogenesis. Genetic polymorphisms were evaluated n 59 patients and 150 controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) followed by polyacrylamide gel electrophoresis and silver nitrate staining. CXCR4 expression was evaluated by immunohistochemistry (IHC) in 37 paraffin tissue samples. Statistical analysis was carried out by Odds ratio (OR) with 95% confidence interval (95%CI), and through Pearson Chi-square, Fisher and Spearman Correlation tests using SPSS statistical software (version 20.0). Case-control study indicated no significant association for CXCL12 (homozygous for variant allele: OR = 2.63, 95% CI 0.51 to 13.39 and variant allele carrier: OR = 1.58, 95% CI 0. 83 to 2.99) and CXCR4 (variant allele carrier: OR = 1.89; 95% CI = 0.58 to 6.22) in relation to TN cancer, even when a combined analysis for risk genotypes was performed (OR = 3.56, 95% CI 0.77 to 16.44). When prognostic parameters were considered, results were not statistically significant in relation to tumor size (CXCL12: p = 0.420; CXCR4: p = 0.925) lymph node metastasis (CXCL12: p = 0.596; CXCR4: p = 0.516) and histological grade (CXCL12: p = 0.192; CXCR4: p = 0.070). IHC analysis demonstrated that CXCR4 expression was more cytoplasmic than at the membrane level and that it was expressed in both normal and tumor tissues, but its cytoplasmic expression was most pronounced in malignant tumor. Therefore, CXCR4 and CXCL12 genes were not susceptibility markers to TN breast cancer, although the results have shown a tendency for genetic variants be more present in the patients group, especially when both genes have been simultaneously considered. The fact that cytoplasmic CXCR4 was more expressed in tumor than in normal tissue must be taken into account and re-evaluated in larger samples, given its prognostic significance

FOXP3 Allelic Variants and Haplotype Structures Are Associated with Aggressive Breast Cancer Subtypes

FOXP3 genetic polymorphisms have been associated with cancer development and prognosis. In this context, the present study aimed to evaluate the g.10403A>G (rs2232365) polymorphisms and g.8048A>C (rs3761548), in aggressive breast cancer (BC) subtypes, including, Luminal B HER2+ (LB), HER2-enriched (HER2+), and triple-negative (TN). Polymerase chain reaction followed by enzymatic restriction was performed to genotyping 117 BC samples and 300 controls. A significant association of AA genotype (g.10403A>G) in relation to BC susceptibility (OR = 1.93; 95% CI = 1.01–3.66; p=0.046) was observed. The GG (g.10403A>G) genotype was correlated with higher proliferation index (Ki-67) in HER2+ subtype (τ = 0.47; p=0.019) and advanced TNM staging in TN (τ = 0.23; p=0.032). A correlation of AA genotype (g.8048A>C) with higher Ki-67 (τ = −0.47; p=0.018) and lower histological grade (τ = 0.39; p=0.026) in HER2+ was also found. GA haplotype was correlated with lower histological grade (τ = −0.15; p=0.009) and higher Ki-67 (τ = 0.43; p=0.036) in HER2+ and advanced staging in TN (τ = 0.29; p=0.044). On the other hand, AC haplotype was correlated with lower Ki-67 (τ = −0.54; p=0.005) and staging (τ = −0.29; p=0.027) in HER2+ and TN respectively. Results showed that FOXP3 influence regarding clinical outcome depends greatly on the BC subtype and indicated this transcription factor as a promising marker in aggressive BC subtypes

FOXP3 Transcription Factor: A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2). FOXP3 (forkhead transcription factor 3) is a marker of regulatory T cells (Tregs), whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548) and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction). Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06) in relation to TNBC susceptibility. Most of the patients (83%) showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P=0.026). In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples

Intussuscepção em adulto - Relato de um caso

  Apresentação de caso de paciente portadora de intussuscepção intestinal, cuja causa era um pseudo tumor inflamatório de jejuno. O diagnóstico de certeza somente foi realizado por laparotomia e exame histopatológico da peça cirúrgica. São tecidos comentários sobre a entidade, após breve revisão bibliográfica

Protein Expression and Codon 72 Polymorphism of TP53 Gene in Triple Negative Breast Cancer

A subgroup of tumor that has received attention is triple-negative breast cancer (TNBC), which presents phenotype of negative estrogen receptor, negative progesterone receptor and has no overexpression of HER2. TP53 acts as a tumor suppressor limiting the proliferation of damaged cells. A polymorphic site (rs1042522) of TP53 encodes either an arginine or a proline amino acid, but its biological significance remains unclear. This study aimed to investigate this variant and its expression in search for a possible involvement in TNBC susceptibility and clinical outcome. Genetic polymorphism was evaluated in 50 patients and 115 controls by PCR based methodology and immunohistochemistry was done with monoclonal antibody. Case-control study showed no positive or negative association (OR= 0.95; CI95%= 0.48-1.89). Comparison of genotypes and clinical outcome showed no significant results. Despite most of patients presented p53 positive staining by immunohistochemistry, there was no significant association in relation to prognostic parameters. Results demonstrated a lack of association between codon 72 polymorphism, susceptibility and prognosis of TNBC. Immunohistochemistry analysis should be done more carefully, since most of the patients had the somatic mutation of p53, which could be an indicator of prognostic value in TNBC