Prevalence and clinical implications of the TP53 pR337H mutation in Brazilian breast cancer patients a systematic literature review

This study assessed the prevalence and clinical implications of the TP53 p.R337H mutation in Brazilian breast cancer patients through a systematic literature review. The literature review was performed in the PubMed, Scientific Electronic Library Online (SciELO), and Medical Literature Analysis and Retrieval System Online (MEDLINE) databases from 1997 to 2018. We used the keyword "R337H" in the search since it resulted in the largest number of published articles on the subject. Initially, we found 75 articles, and, after reviewing the titles and abstracts, we selected 18 studies investigating the prevalence of the TP53 p.R337H mutation in breast cancer patients and its clinical implications. The reading of the full texts led to the inclusion of seven studies. The studies were carried out in the states of São Paulo, Rio Grande do Sul, Rio de Janeiro, and Bahia. The TP53 p.R337H mutation was detected in 87 (4.8%) of the 1.789 women with breast cancer investigated. The prevalence of the TP53 p.R337H mutation in the selected studies ranged from 0.5 to 8.6%. These findings highlight the recommendation for screening the R337H variant in breast cancer patients in Brazil and suggest the need for new research addressing the clinical and prognostic aspects of breast cancer patients with TP53 p.R337H mutation-positive.

Association between diabetes and vestibular dysfunction: an integrative review / Associação entre diabetes e disfunções do sistema vestibular: revisão integrativa

ABSTRACT Purpose: to identify, in the literature, the factors associated with the development of vestibular dysfunctions in individuals with type 2 diabetes mellitus (DM2). Methods: an integrative review of the literature, whose survey was conducted in the databases ISI, SciELO, LILACS and PubMed, using the following descriptors: "type 2 diabetes mellitus", "vertigo", "dizziness", and "vestibular diseases". Articles published in the last 10 years that answered the research question ("What factors are associated with the development of vestibular disorders in individuals with DM2?") were included in the study. Results: the search returned 426 articles, 10 of which met the eligibility criteria. Most of the participants of the selected studies who had vestibular dysfunctions were women over 40 years old and had more than one comorbidity related to DM2, the main one being the systemic arterial hypertension (SAH). According to the literature, the physiology of the inner ear allows small glucose alterations to influence its normal functioning, which makes diabetic individuals more susceptible to developing vestibular dysfunctions. Conclusion: according to this study, DM2 can trigger or contribute to the manifestation of vestibular dysfunction, whose main associated factors are advanced age, female gender, and various comorbidities, as dyslipidemia, SAH and metabolic syndrome.

RESUMO Objetivo: identificar na literatura os fatores que estão associados ao desenvolvimento de disfunções vestibulares em indivíduos com diabetes mellitus tipo 2 (DM2). Métodos: trata-se de uma revisão integrativa da literatura, cuja busca foi realizada nas bases de dados ISI, Scielo, LILACS e PubMed, sendo utilizados os descritores: "type 2 diabetes mellitus", "vertigo", "dizziness" e "vestibular diseases". Foram incluídos artigos publicados nos últimos dez anos e que respondessem a seguinte questão: quais fatores estão associados ao desenvolvimento de disfunções vestibulares em indivíduos com DM2? Resultados: a busca resultou em 426 artigos, sendo que 10 atenderam aos critérios de elegibilidade. A maioria dos participantes dos estudos selecionados que apresentaram disfunções vestibulares eram do sexo feminino, idade superior a 40 anos e possuíam mais de uma comorbidade associada a DM2, sendo a principal, a hipertensão arterial sistêmica (HAS). De acordo com a literatura, a fisiologia da orelha interna permite que pequenas alterações de glicose influenciem seu funcionamento normal, o que torna os indivíduos diabéticos mais suscetíveis a desenvolverem disfunções vestibulares. Conclusão: o presente estudo constatou que a DM2 pode desencadear ou contribuir para a manifestação da disfunção vestibular, tendo como principais fatores associados a idade avançada, o sexo feminino e comorbidades diversas, tais como dislipidemia, HAS e síndrome metabólica.

Association of the TP53 codon 72 polymorphism and breast cancer risk: a meta-analysis.

This study was conducted in order to investigate the implications of the R72P polymorphism in the TP53 gene in breast cancer risk. The enlightenment of this matter might provide a piece of information about the potential implications of this polymorphism in patient risk. A meta-analysis was conducted considering a large sample size from studies with conflicting results on the R72P polymorphism in breast cancer patients. Relevant studies were selected from PubMed and SciELO databases for data extraction and statistical analysis. Database was built according to the continent and considering the genotype frequencies, sample size and genotyping methodology. The dominant models (RR vs RP + PP and RR + RP vs. PP), homozygous (RR vs. PP), heterozygous (RR vs. RP and RP vs. PP) and the allele (R vs. P) were used. Genotype frequencies were summarized and evaluated by χ(2) test of heterogeneity in 2×2 contingency tables with 95% CIs. Odds Ratios (OR) were calculated with a fixed-effect model (Mantel-Haenszel) or a random-effect model (DerSimonian-Laird) if the studies were considered homogeneous (P > 0.05) or heterogeneous (P < 0.05), respectively, using BioEstat® 5.0 software. Supported by a large sample size composed by 25,629 cases and 26,633 controls from 41 studies, we found significant association between the R72P polymorphism in the TP53 gene and the breast cancer risk. The overall data shows an increased risk due to the P allele dominant model, but not in Asia where the risk was associated with the R allele and R dominant model.

Association between the HLA-G molecule and lymph node metastasis in papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and can present as lymph node metastasis in 30 to 65% of cases when initially diagnosed. High frequency recurrence, distant metastasis and treatment resistance can be found in cases of PTC so early diagnosis and treatment are critical for improved prognosis and better survival rates. The characterization of new biomarkers has proved useful for the diagnosis and follow-up of these patients. HLA-G is a non-classical HLA class I molecule whose expression in cancer cells has been associated with tumor evasion of immune response. Therefore, the aim of this study was to investigate the HLA-G expression and its clinical significance in PTC. Paraffin-embedded thyroid biopsies of 70 PTC patients (40 of whom had presented with metastasis) were evaluated. HLA-G-staining was observed in tumor cells in PTC, and the HLA-G expression was significantly associated with an increased occurrence of lymph node metastasis (p=0.0006) and capsular invasion (p=0.02). This preliminary data shows the HLA-G expression in thyroid carcinoma specimens for the first time and suggests that this expression could impair efficient anti-tumor immunity in PTC. This would indicate that HLA-G could have an independent prognostic value in PTC, principally for tumor recurrence.

Impacto do fenótipo triplo-negativo no prognóstico de pacientes com câncer de mama de uma unidade de referência no Brasil central / Impact of triple negative phenotype on prognosis of breast cancer patients from a reference cancer unity in the central of Brazil

Introdução: o câncer de mama triplo-negativo inclui os tumores que não expressam receptores de estrógenos, receptores de progesterona e HER2. O subtipo triplo-negativo apresenta características mais agressivas, como aparecimento em idade mais precoce, estágio avançado ao diagnóstico, alta graduação histológica e nuclear, alto índice mitótico, maior frequência de metástases regionais e à distância, além de menor sobrevida. Objetivo: comparar os aspectos clínicos e patológicos de 345 pacientes com carcinomas mamários tratadas em um hospital de referência na região Centro-oeste do Brasil, a fim de avaliar o impacto do fenótipo triplo-negativo no prognóstico das pacientes. Metodologia: as pacientes foram selecionadas no Laboratório de Anatomia Patológica da instituição e os dados clínicos e patológicos coletados a partir dos respectivos prontuários. A análise estatística empregou análise univariada e análise de sobrevida pelo método de Kaplan-Meier e Log-rank. Resultados: os fatores prognósticos clássicos foram comprovados para o grupo, incluindo comprometimento de linfonodos regionais (p<0,001), metástase à distância (p<0,001) e tamanho do tumor (p<0,001). Quando os tumores, distribuídos em dois grupos (TN e NTN), foram comparados, diferenças estatisticamente significativas foram observadas com relação ao grau nuclear (p<0,0001) e à sobrevida em cinco anos (p<0,0001), que variou de 70,3% para as pacientes NTN a 47,1% para as pacientes TN. Conclusão: nossos resultados confirmaram o perfil mais agressivo dos tumores TN que, independentemente dos fatores prognósticos clássicos dos carcinomas de mama, cursam com maior agressividade e maior taxa de mortalidade, requerendo assim maior atenção assistencial.

Introduction: Triple-negative breast cancers are tumors that don't express estrogen receptors, progesterone receptors and HER2. The triple-negative phenotype exhibits more aggressive characteristics, including early onset, high stage on diagnosis, elevated nuclear grade, high mytotic index, agressive patterns of regional and distant metastasis, besides poor prognosis. Objective: To compare the clinical and pathological aspects of a group with 345 breast cancer patients treated in a referral hospital in the center of Brazil, in order to compare the impact of triple-negative phenotype on the patient prognosis. Methods: Patients were selected in the Pathology Laboratory of the institution. Clinical and pathological data were collected from the respective clinical files. Statistical methods comprised univariate analysis and survival curves were generated by using Kaplan-Meier and Log-rank tests. Results: Classic prognostic factors were confirmed for the whole group, including regional lymph nodes metastasis (p<0.001), distant metastasis (p<0.001) and tumor size (p<0.001). By comparing the two groups of breast tumors (TN and NTN), significant statistical differences were observed concerning nuclear grade (p<0.0001) and five year survival (p<0.0001), which varied from 70.3% for NTN patients to 47.1% for TN patients. Conclusion: Our results reinforce the aggressive profile of triple-negative breast cancer that, despite of the classic prognostic factors described for breast cancer, evolves with higher aggressiveness and elevated mortality rates, requiring special attention

Low doses of gamma ionizing radiation increase hprt mutant frequencies of TK6 cells without triggering the mutator phenotype pathway

The TK6 lymphoblastoid cell line is known to be mismatch repair (MMR) and p53 proficient. Deficiency in MMR results in a mutator phenotype characterized by microsatellite instability (MSI) and increased hprt mutant frequency (MF). Increased hprt MF is also a biomarker of effect for exposure to ionizing radiation. In order to test if a mutator phenotype could be induced by low doses of gamma ionizing radiation, an hprt cloning assay and a MSI investigation were performed after radiation exposure. The spontaneous MF was 1.6 x 10-6. The groups exposed to 0.2, 0.5 and 1.0 Gy had hprt MFs of 2.3, 3.3 and 2.2 x 10-6, respectively. The spontaneous MSI frequency per allele in non-selected cells was 5.4 x 10-3, as evidenced at the loci D11S35, nm23-H1, D8S135 and p53. MSI frequencies in the groups exposed to 0.2, 0.5 and 1.0 Gy were found to be < 4.7, < 7.7 and < 12 x 10-3, respectively. The frequencies of hprt mutants and MSI found in this study suggest that low doses of ionizing radiation increase hprt mutant frequency without triggering the mutator phenotype pathway.

Detection of mutator phenotype in Brazilian patients with acute and chronic myeloid leukemia

The multisteps of tumorigenesis involve the classic chromosomal instability and the mutator phenotype pathways featured by a predisposition to acquire mutations in tumor suppressor genes and oncogenes. Expansion and contraction of microsatellite sequences due to a deficient mismatch repair system are a marker of the mutator phenotype. Controversial results regarding the extent of microsatellite instability (MSI) have been reported in the development and progression of myeloid malignancies. Here, we investigated MSI and loss of heterozygosity (LOH) frequencies at the microsatellite loci BAT-26, D7S486, D8S135, ANK1, IFNA, TP53 and bcr of 19 Brazilian patients with acute (AML) and chronic myeloid leukemia (CML). One AML patient and one CML patient were categorized as having a high degree of microsatellite instability (MSI-H), corresponding to 10.5 percent (2/19) of all patients. LOH at loci BAT-26 and TP53 was present in 30 percent of the patients with AML alone. Despite the small sample size, our results suggest that the mutator phenotype, as verified by MSI frequency, could play a role in the leukemogenesis of a small subset of patients with myeloid leukemia.

Human dendritic cells mediate anti-tumor activity against hematopoietic tumor cells without direct contact and Fas/FasL killing pathway.

During maturation, the capacity of dendritic cells (DCs) to uptake and process antigens becomes diminished while the expression of MHC molecules and costimulatory molecules is up-regulated. These phenotypic changes make DCs potent antigen presenting cells with the ability to initiate and modulate immune responses. Recent findings have shown that DCs can mediate direct cytotoxicity toward tumor cells. Here, we investigated the effect of monocyte derived DC (moDC) on hematopoietic tumor cells by assessing the uptake of [methyl-3H]thymidine (3H-TdR), JAM test (radiometric assay for DNA fragmentation) and 51Cr-release assay. We found that moDCs significantly inhibited the growth of 6 tumor cell lines and stimulated another 4 cell lines independently of the expression of Fas protein. MoDCs also inhibited the proliferation of tumor cells in transwell culture, including two cell lines that were driven to proliferate by direct contact with moDCs. Apoptosis, but not cytolysis, was detected in all the cell lines inhibited by moDCs. In contrast, no cytostatic or cytotoxic effect was detected on K562 cells (chronic myeloid leukemia) and BY94 cells (sporadic Burkitt's lymphoma). The inhibitory activity of moDCs on Fas-expressing tumor cells fully persisted after the neutralization of FasL. Accordingly, there was no detection of FasL protein or FasL mRNA expression in moDC. These results suggest that moDCs can mediate a direct anti-tumor activity against hematopoietic tumor cells through cytostasis in absence of contact or through apoptosis without triggering the Fas/FasL pathway.