EZH2 expression is dependent on MYC and TP53 regulation in diffuse large B-cell lymphoma.

EZH2 is an important epigenetic regulator, but its role in diffuse large B-cell lymphoma (DLBCL) pathogenesis and its relationship with MYC, BCL2, and TP53 expression, chromosomal rearrangements, and clinical features are still poorly understood. So, we investigated EZH2 expression and its associations with the immunophenotypic presentations, including MYC, BCL2, and TP53 expression, MYC, BCL2, and BCL6 translocation status, clinicopathological features, and therapeutic response to R-CHOP in a series of 139 DLBCL cases. EZH2 positivity was associated with MYC and TP53 expression (p = 0.0002 and p = 0.0000, respectively) and to high proliferative index (Ki67>70%, p = 0.0082). No associations were found among EZH2 expression and chromosomal translocation status. The non-germinal center (nGC) DLBCL presented most of associations observed in the general sample; however, only TP53 immunodetection showed associations with EZH2 expression in the germinal center (GC) DLBCL. EZH2 expression had no impact on therapeutic efficacy in R-CHOP-treated patients. In conclusion, EZH2 seems to be upregulated by MYC, to rely on TP53 alterations, and is associated with high proliferative tumors in DLBCL, which might be dependent on GC or nGC subclassifications. Furthermore, it is not a therapeutic efficacy marker to R-CHOP in our series.

The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma.

Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG.

Mammary hibernoma: A case report of a rare disease / Hibernomamamário: relato de caso de uma doença rara

Abstract Mammary hibernomas are extremely rare benign tumors composed of brown fat cells, with only five cases previously reported in the literature. We report the case of a 42- year-old female patient with a painless growing mass in her right breast. A partial mastectomy was performed, and the diagnosis of hibernoma was confirmed by the histological features and the immunohistochemical profile. Although hibernoma is a benign tumor, its main differential diagnoses include aggressive lesions, making the accurate diagnosis essential to provide adequate care to the patient.

Resumo Hibernomas mamários são tumores benignos extremamente raros compostos por gordura marrom, com apenas cinco casos previamente relatados na literatura. Relatamos o caso de uma paciente do sexo feminino, de 42 anos de idade, apresentando- se com uma massa indolor em sua mama direita. Realizou-se uma mastectomia parcial e o diagnóstico de hibernomamamário foi confirmado pelo padrãomorfológico e pelo perfil imuno-histoquímico. Embora hibernomas constituamneoplasias benignas, seus principais diagnósticos diferenciais incluem lesões agressivas, sendo o diagnóstico acurado extremamente importante para o correto manejo clínico do paciente.

Mammary Hibernoma: A Case Report of a Rare Disease.

Mammary hibernomas are extremely rare benign tumors composed of brown fat cells, with only five cases previously reported in the literature. We report the case of a 42-year-old female patient with a painless growing mass in her right breast. A partial mastectomy was performed, and the diagnosis of hibernoma was confirmed by the histological features and the immunohistochemical profile. Although hibernoma is a benign tumor, its main differential diagnoses include aggressive lesions, making the accurate diagnosis essential to provide adequate care to the patient.

Hibernomas mamários são tumores benignos extremamente raros compostos por gordura marrom, com apenas cinco casos previamente relatados na literatura. Relatamos o caso de uma paciente do sexo feminino, de 42 anos de idade, apresentando-se com uma massa indolor em sua mama direita. Realizou-se uma mastectomia parcial e o diagnóstico de hibernoma mamário foi confirmado pelo padrão morfológico e pelo perfil imuno-histoquímico. Embora hibernomas constituam neoplasias benignas, seus principais diagnósticos diferenciais incluem lesões agressivas, sendo o diagnóstico acurado extremamente importante para o correto manejo clínico do paciente.

Histopathological regression of gastric adenocarcinoma after neoadjuvant therapy: a critical review.

As the perioperative chemotherapy has been widely implemented on the management of gastric cancer patients, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Tumor histological response to preoperative therapy has been graded by various systems in order to categorize the amount of regressive changes induced by chemotherapy in relation to residual tumor. In this context, tumor regression grading (TRG) systems might provide important prognostic information as the variety of tumor response may imply on different clinical outcomes with impact in survival rates. Moreover, gastric cancer behavior varies enormously upon individual factors such as histological classification and tumor anatomic site of involvement that have been shown to affect the TRG interpretation. On the other hand, some studies have assessed the role of molecular markers as a predictor of tumor response to neoadjuvant chemotherapy in terms of TRG. Thus, the aim of this review is to evaluate how TRG has been interpreted in gastric cancer, discuss their clinical and prognostic relevance and also address the molecular markers involved in this process.

CDKN2A promoter hypermethylation in astrocytomas is associated with age and sex.

CDKN2A promoter hypermethylation has been widely related to many cancers. In astrocytomas, although CDKN2A (p16(INK4A) protein) is often inactivated, there are still some controversial issues regarding the mechanism by which this alteration occurs. Thus, we analyzed a series of astrocytomas to assess the association between CDKN2A expression and methylation of grade I-IV tumors (WHO) and clinicopathological parameters. DNA extracted from formalin-fixed paraffin-embedded material of 93 astrocytic tumors was available for CDKN2A promoter methylation analysis and p16(INK4A) expression by methylation-specific PCR and immunohistochemistry, respectively. A strong negative correlation between nuclear and cytoplasmic immunostaining and CDKN2A promoter methylation was found. Additionally, a significant negative correlation between CDKN2A promoter methylation and age was observed; also, female patients had statistically more CDKN2A methylated promoters (p = 0.036) than men. In conclusion, CDKN2A inactivation by promoter methylation is a frequent event in astrocytomas and it is related to the age and sex of patients.

Interleukin polymorphisms and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.

AIM: Interleukin polymorphisms and Helicobacter pylori infection are believed to play critical roles in DNA methylation, a process frequently associated with carcinogenesis. The aim of this study was to determine the associations between interleukin polymorphisms and methylation status of three genes related to gastric cancer. Furthermore, the influence of the H. pylori strains was evaluated. MATERIALS & METHODS: 75 gastric tumor samples had the DNA extracted for interleukin polymorphisms genotyping by PCR-RFLP, promoter methylation by MS-PCR and detection and subtyping of H. pylori by PCR. RESULTS: In the cardia tumors, methylation in the COX-2 promoter was associated with IL1RN*2 (p = 0.015), and the associated genotypes IL1B511T + IL1RN*2 seem to be important in the methylation of COX-2 (p = 0.013), especially in the presence of cagA(+) (p = 0.026) and vacAs1 (p = 0.025) H. pylori strains. The associated genotypes IL6 CC+TNF GG seem to be involved in the unmethylation of CDKN2A (p = 0.046), along with H. pylori cagA(+) infection. CONCLUSION: DNA methylation in gastric cancer seems to be influenced by the presence of interleukin polymorphisms and by the H. pylori cagA/vacAs1m1 strains.

TP53 codon 72 and intron 3 polymorphisms and mutational status in gastric cancer: an association with tumor onset and prognosis.

Although TP53 alterations have been studied in human tumors, data considering the role of two common TP53 polymorphisms (Pro72Arg in codon 72 and Ins16bp in intron 3) and their associations with TP53 mutations in gastric cancer are very limited. Thus, we analyzed these parameters taking into consideration the clinicopathological data. DNA from 106 gastric tumor samples was available for TP53 Pro72Arg and TP53 Ins16bp polymorphism genotyping by PCR-RFLP and PCR, respectively. The mutational status of the TP53 exons 5-7 was assessed by the single-strand conformational polymorphism test. The TP53 72ArgArg genotype was statistically associated with patients aged ≥65 years (p = 0.039), and the intron 3 A2A2 genotype was correlated with late-stage tumors (III and IV; p = 0.043). Considering both polymorphisms, a negative correlation between the TP53 Pro-A1 haplotype and age <65 years (r = -0.211; p = 0.030) was found. Taking into account the TP53 mutations, the Pro/Pro genotype was positively correlated with the presence of exon 7 mutations (p = 0.049), and a correlation between this genotype and the number of mutations in TP53 was observed (p = 0.019). This study corroborates the understanding of TP53 polymorphisms in gastric carcinogenesis, especially regarding the genetic features in tumor onset and prognosis.

MTHFR C677T polymorphism and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.

MTHFR C677T and Helicobacter pylori infection are believed to play critical roles in the DNA methylation process, an epigenetic feature frequently found in gastric cancer. The aim of this study was to verify the associations between the MTHFR C677T polymorphism and the methylation status of three gastric cancer-related genes. The influence of H. pylori strains was also assessed. DNA extracted from 71 gastric tumor samples was available for MTHFR C677T genotyping by PCR-RFLP, promoter methylation identification by MS-PCR and H. pylori detection and posterior subtyping (cagA and vacA genes) by PCR. In the distal tumors, a positive correlation was found between the methylation of CDKN2A and the allele T carriers (r=0.357; p=0.009). Considering the eldest patients (age ≥60 years old), this correlation was even higher (r=0,417; p=0.014). H. pylori infection by highly pathogenic strains (cagA+/vacAs1m1) was also found correlated to promoter methylation of CDKN2A and the allele T carriers in distal tumors (r=0.484; p=0.026). No significant correlation was verified between MTHFR C677T genotype and promoter methylation status when we analyzed the general sample. DNA methylation in CDKN2A associated to the MTHFR 677T carrier is suggested to be a distal tumor characteristic, especially in those 60 years old or older, and it seems to depend on the infection by H. pylori cagA/vacAs1m1 strains.