Aspectos histológicos, genéticos y moleculares de las lesiones preneoplásicas de la mucosa gástrica / Histological, genetic and molecular aspects of preneoplastic lesions of the gastric mucosa

Siendo el cáncer gástrico la 3ª causa de muerte por cáncer en Chile, y existiendo estrategias de tamizaje consistentes en pesquisa de lesiones preneoplásicas de la mucosa gástrica, es relevante conocer los aspectos genéticos y moleculares que puedan ser aplicados, en la optimización de dichas estrategias a grupos de mayor riesgo. El objetivo de este manuscrito fue revisar la evidencia actual en los aspectos señalados, y de la inmunohistoquímica de 4 marcadores (p53, CDX2, MUC2 y S100A9) en la mucosa gástrica normal y en las lesiones preneoplásicas de la misma.

SUMMARY: Since gastric cancer is the 3rd leading cause of death from cancer in Chile, and there are screening strategies consisting of screening for preneoplastic lesions of the gastric mucosa, it is important to know certain genetic and molecular aspects that can be applied in optimizing these strategies for higher risk groups. The aim of this manuscript was to review the current evidence on the aforementioned aspects, and on the immunohistochemistry of 4 markers (p53, CDX2, MUC2 and S100A9) in normal gastric mucosa and in its preneoplastic lesions.

Chronic prostatitis alters the prostatic microenvironment and accelerates preneoplastic lesions in C57BL/6 mice

BACKGROUND: Chronic prostatitis has been supposed to be associated with preneoplastic lesions and cancer development. The objective of this study was to examine how chronic inflammation results in a prostatic microenvironment and gene mutation in C57BL/6 mice. METHODS: Immune and bacterial prostatitis mouse models were created through abdominal subcutaneous injection of rat prostate extract protein immunization (EAP group) or transurethral instillation of uropathogenic E. coli 1677 (E. coli group). Prostate histology, serum cytokine level, and genome-wide exome (GWE) sequences were examined 1, 3, and 6 months after immunization or injection. RESULT: In the EAP and E. coli groups, immune cell infiltrations were observed in the first and last months of the entire experiment. After 3 months, obvious proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) were observed accompanied with fibrosis hyperplasia in stroma. The decrease in basal cells (Cytokeratin (CK) 5+/p63+) and the accumulation of luminal epithelial cells (CK8+) in the PIA or PIN area indicated that the basal cells were damaged or transformed into different luminal cells. Hic1, Zfp148, and Mfge8 gene mutations were detected in chronic prostatitis somatic cells. CONCLUSION: Chronic prostatitis induced by prostate extract protein immunization or E. coli infection caused a reactive prostatic inflammation microenvironment and resulted in tissue damage, aberrant atrophy, hyperplasia, and somatic genome mutation.

Genotyping of High Risk Human Papillomavirus (HPV) Among Cervical Precancer and Cancer Patients.

Introduction: Human papillomavirus (HPV) is a DNA virus which has tropism for epithelial cells, is the major etiological factor for development of cervical precancerous and cancerous lesions. Nearly 100 diff erent types of HPV have been characterized and thereare a large number of other types. HPV infection is one of the most common causes of sexually transmitted disease in both men and women worldwide. It is associated with a variety of clinical conditions that range from innocuous lesions to cancer. Genital HPV types are divided into high and low-risk types, according to the oncogenic potential. Molecular and epidemiologic studies have solidifi ed the association between high risk HPV types (especially HPV-16 and HPV-18) and cervical squamous cell carcinoma. HPV infection is often transient and self-limiting but infection may persists and progress to high grade lesions and cancer. In addition to persistent high-risk HPV infection, other viral factors such as high viral loads, HPV variants, infections with multiple high-risk HPV types and genetic predisposition contribute to the development of cervical cancer. Th e aim of the present study was to detect HPV DNA and identify high risk HPV genotype among women having cervical intraepithelial neoplasia and carcinoma and to evaluate potential effi cacy of prophylactic HPV vaccine. Methods: Cervical swab from histopathologically diagnosed CIN (n=51) and carcinoma (n=39) patients were taken and high risk HPV DNA was detected by HC II assay. Polymerase Chain Reaction was used to identify high risk HPV genotype. Result: HPV DNA was detected in 41 (45.56%) patients by HC II assay. HPV type 16 was detected in 27 (81.82%) followed by type 18 in 3 (9.09%) and type 45 in 2 (6.06%) cases of cervical carcinoma. Among precancerous cases, only type 16 was detected. Conclusion: Knowledge based on HPV prevalence and genotype could be used to predict the effi cacy of cost eff ective prophylactic vaccine, introduction of newer generation vaccine and management of cervical carcinoma.

Violence against adolescents: an analysis based on the categories gender and generation / La violencia contra adolescentes: un análisis a la luz de las categorías género y generación / Violência contra adolescentes: uma análise à luz das categorias gênero e geração

Exploratory and descriptive study based on quantitative and qualitative methods that analyze the phenomenon of violence against adolescents based on gender and generational categories. The data source was reports of violence from the Curitiba Protection Network from 2010 to 2012 and semi-structured interviews with 16 sheltered adolescents. Quantitative data were analyzed using SPSS software version 20.0 and the qualitative data were subjected to content analysis. The adolescents were victims of violence in the household and outside of the family environment, as victims or viewers of violence. The violence was experienced at home, mostly toward girls, with marked overtones of gender violence. More than indicating the magnitude of the issue, this study can give information to help qualify the assistance given to victimized people and address how to face this issue.

Objetivo Analizar la violencia contra los adolescentes a la luz de las categorías de género y generación. Método Estudio exploratorio, descriptivo, de abordaje cuantitativo y cualitativo que. Las fuentes de datos fueron las denuncias de violencia mantenidos por la Red de Protección en Curitiba entre los años 2010-2012 y entrevistas semi-estructuradas con 16 adolescentes alojados. Las variables cuantitativas se analizaron mediante el programa SPSS y los cualitativos por la análisis de contenido. Resultados Los adolescentes fueron sometidos a la violencia en el hogar y en el exterior, como víctimas o espectadores. La violencia fue más frecuente en el hogar, centrándose principalmente en las chicas con matices marcados de violencia de género. Conclusión Más que encontrar la magnitud del problema, el estudio puede servir de base para calificar la asistencia a las personas víctimas de este fenómeno.

 .

Objetivo Analisar a violência contra o adolescente à luz das categorias gênero e geração. Método Estudo exploratório, descritivo, de abordagem quantitativa e qualitativa. As fontes de dados foram as notificações de violência da Rede de Proteção do município de Curitiba, de 2010 a 2012, e entrevistas semiestruturadas com 16 adolescentes abrigados. As variáveis quantitativas foram analisadas pelo software SPSS e os dados qualitativos através da análise de conteúdo. Resultados Os adolescentes foram submetidos à violência no ambiente doméstico e fora dele, como vítimas ou como espectadores. Prevaleceu no domicílio, incidindo principalmente sobre as meninas, com marcada conotação de violência de gênero. Conclusão Mais que constatar a magnitude do problema, o estudo pode fornecer subsídios para qualificar a assistência prestada aos sujeitos vitimizados e subsidiar o enfrentamento do fenômeno. .

An upward trendiin dna p16ink4a methylation patern and high risk hpv infectionn according to the severity of the cervical lesion / Padrão de metilação do gene P16INK4A e de infecções por HPV de alto risco acompanham a evolução de lesões cervicais

SUMMARY High-risk human papillomavirus (hr-HPV) infection is necessary but not sufficient for cervical cancer development. Recently, P16INK4A gene silencing through hypermethylation has been proposed as an important cofactor in cervical carcinogenesis due to its tumor suppressor function. We aimed to investigate P16INK4A methylation status in normal and neoplastic epithelia and evaluate an association with HPV infection and genotype. This cross-sectional study was performed with 141 cervical samples from patients attending Hospital Moncorvo Filho, Rio de Janeiro. HPV detection and genotyping were performed through PCR and P16INK4A methylation by nested-methylation specific PCR (MSP). HPV frequency was 62.4% (88/141). The most common HPV were HPV16 (37%), HPV18 (16.3%) and HPV33/45(15.2%). An upward trend was observed concerning P16INK4A methylation and lesion degree: normal epithelia (10.7%), low grade lesions (22.9%), high grade (57.1%) and carcinoma (93.1%) (p < 0.0001). A multivariate analysis was performed to evaluate an association between methylation, age, tobacco exposure, HPV infection and genotyping. A correlation was found concerning methylation with HPV infection (p < 0.0001), hr-HPV (p = 0.01), HSIL (p < 0.0007) and malignant lesions (p < 0.0001). Since viral infection and epigenetic alterations are related to cervical carcinoma, we suggest that P16INK4A methylation profile maybe thoroughly investigated as a biomarker to identify patients at risk of cancer. .

RESUMO É reconhecido que infecções por papilomavírus humanos de alto risco (HPV) são causa necessária, mas não suficiente para o desenvolvimento do câncer cervical. Recentemente, estudos de silenciamento gênico apontaram que a hipermetilação do gene p16INK4A é importante co-fator para a carcinogênese cervical, eliminando a função supressora de tumor da proteína p16 em lesões malignas. Entretanto poucos estudos avaliaram a relação da metilação com a progressão da doença. Nosso objetivo foi investigar o padrão de metilação do gene P16INK4A em diferentes graus de lesão cervical e sua associação com a infecção por diferentes tipos de HPV. Nosso estudo de corte transversal avaliou 141 amostras cervicais de pacientes atendidas no Hospital Moncorvo Filho, Rio de Janeiro. A detecção e tipagem do HPV foi realizada pela técnica de reação em cadeia da polimerase (PCR), e a metilação do gene P16INK4A pela PCR-metilação específica em formato nested (MSP). A frequência de HPV foi de 62,4% (88/141). O tipo mais prevalente foi o HPV16 (37%), seguido pelo HPV18 (16,3%) e HPV33/45 (15,2%). Curva ascendente foi observada quanto ao padrão de metilação do gene P16INK4A e o grau da lesão: a metilação foi identificada em somente 10,7% das amostras de epitélio normal, em 22,9% das lesões de baixo grau, em 57,1% das lesões de alto grau e em 93,1% dos carcinomas (p < 0,0001). Foram feitas análises univariada e multivariada a fim de correlacionar metilação, idade, exposição ao tabaco, infecção e genótipo de HPV. Foi encontrada correlação da metilação com a infecção pelo HPV (p < 0,0001), genótipos de alto risco (p = 0,01), ...

Evaluation of DNA damage in oral precancerous and squamous cell carcinoma patients by single cell gel electrophoresis.

Context: Single cell gel electrophoresis (SCGE) or "comet assay" is a rapid and very sensitive fluorescent microscopic method for detecting various forms of DNA damage at individual cell level. Aims: The aim of the present study was to detect the extent of DNA damage in oral cancer, oral submucous fibrosis (OSMF) and leukoplakia in comparison to normal individual. Settings and Design: A total of 44 consecutive patients with oral cancer (n=26), leukoplakia (n=12) and OSMF (n=6) and 10 healthy normal volunteers with normal oral epithelia (controls) were recruited from Dr. R. Ahmed Dental College and Hospital and were assessed for the extent of DNA damage using SCGE following clinical diagnosis. Materials and Methods: Peripheral blood was collected by venepuncture and comet assay was performed using SCGE. Mean tail length was compared between diagnostic groups and between different oral habit groups using t-tests and analysis of variance (ANOVA). Pearson's product moment correlation was used to examine the linear association between the extent of DNA damage and oral habit pack-years. Scheffe's pair-wise test was employed to adjust for multiple comparisons. Results: None of the controls were associated with any oral habits. Mean (±SD) tail lengths (in mm) for cancer (24.95 ± 5.09) and leukoplakia (12.96 ± 2.68) were significantly greater than in controls (8.54 ± 2.55, P<0.05). After adjustment, well-, moderately, and poorly differentiated carcinomas had significantly greater tail length than controls. Whereas the extent of DNA damage in cancer cases was significantly greater in leukoplakia than in compared to OSMF (11.03 ± 5.92), the DNA damage in latter was not different from controls. DNA damage for people with any oral habit (19.78 ± 7.77) was significantly greater than those with no habits (8.54 ± 2.55; P<0.0001). Conclusions: DNA damage measured by SCGE is greater in leukoplakia and squamous cell carcinoma, but not in OSMF. Deleterious oral habits are also associated with greater DNA damage.

Detección y tipificación de virus papiloma humano en lesiones preneoplásicas de cuello uterino / Human papillomavirus genotyping of cervical uterine preneoplastic lesions in a high risk area

The relationship between human papillomavirus (HPV) and uterine cervical cancer (UCC) is widely known and accepted. Aim: To determine the frequency of genotypes of HPV in cervical preneoplastic lesions in a high risk area of UCC. Material and Methods: Using a combination of PCR and Reverse Line Blot technique, 235 formalin fixed paraffin embedded samples, with diagnosis of low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL) were genotyped. Results: HPV was detected in 61.2 percent of LSIL and 78.1 percent of HSIL. The main genotypes found were HPV 16, 18, 31, 45, 56 y 58. HPV 16 was the most common in both LSIL (18.1 percent) and HSIL (36.9 percent). HPV 16 or 18 were present in 25.1 percent and 47.1 percent of the LSIL and HSIL respectively. In both LSIL and HSIL, the predominant viral genotypes were those types classified as with a high oncogenic risk. Conclusions: HPV genotypes 16, 18, 31, 45, 56 y 58 were the most common in our series. HPV 16 and 18, viral types with high oncogenic risk and included in commercial vaccines, were found in 25.1 percent and 47.1 percent of LSIL and HSIL, respectively.

Alteraciones genéticas en lesiones preneoplásicas y neoplásicas de la vesícula biliar / Genetic alterations in preneoplastic and neoplastic injuries of the gallbladder

This article aims to review the most relevant morphological and molecular aspects involved in gallbladder (GB) cancer. In Chile, gallbladder cancer is the main cause of death due to cancer, among women older than 40 years. However, there is almost none information about the morphological changes and the genetic alterations in-volved in the beginning and development of this neoplasia. Two carcinogenic ways have been described. The sequence adenoma-carcinoma is accepted to be less frequent and important. The most important is the sequence where a metaplasia evolves to displasia that progresses to carcinoma in situ and fnally it becomes invasive. This progress requires 10 to 15 years approximately. During this time, a continue progression of injuries have been described. Molecular research studies show genetic anomalies in some genes which are temporary events in preneoplastic injuries of the gallbladder. Some of them even exist before the frst morphological changes, while the expression of tumor suppressor genes like p53, adhesion molecules and oncogenes, among others, can be related to late GB carcinogenesis. The K-ras gene seems to play a role in this neoplasia, mainly in those that present an abnormal biliopancreatic union. The microsatelital instability has been found in a small subset of preneoplastic and neoplastic lesions. The existence of methylation in the promotor gene areas has been related to the cellular proliferation, invasion and metastasis and also in cases of chronic cholecystitis, suggesting that this epigenetic phenomenon represents a crucial early event in GB carcinogenesis.

GST null genotype and antioxidants: Risk indicators for oral pre-cancer and cancer.

Objectives : This study was undertaken to detect the gene polymorphism of detoxification enzymes and estimate the antioxidant enzyme status in patients with oral cancer, oral leukoplakia and oral submucous fibrosis (OSF). Materials and Methods : The GSTM1 and GSTT1 gene polymorphism was evaluated using polymerase chain reaction; the antioxidant enzyme was estimated using biochemical methods. Statistical analyses were performed using student t-test and odds-ratio to estimate relative risk (RR). Results : The RR at 95% confidence interval (CI) for GSTM1 and GSTT1 was statistically significant for all groups. The mean values of glutathione were significantly raised in all groups. The mean values of ceruloplasmin and malonaldehyde was statistically significant among cancer and OSF patients but was insignificant in smokers and cases with leukoplakia. Conclusion : Several genes perform the same function which implies the need to test for several genetic polymorphisms to identify individuals at high risk. The level of antioxidant enzymes correlate with the degree of oxidative damage. The need for further studies is emphasised.

Prevalence of c-myc expression in breast lesions associated with microcalcifications detected by routine mammography / Expressão de c-myc em lesões mamárias associadas a microcalcificações detectadas por mamografia de rotina

CONTEXT AND OBJECTIVE: Genetic abnormalities in cell proliferation-regulating genes have been described in premalignant lesions. The aims here were to evaluate c-myc protein expression in non-palpable breast lesions associated with microcalcifications, detected by screening mammography, and to compare these results with histopathological, clinical and epidemiological variables. DESIGN AND SETTING: Analytical cross-sectional study, with retrospective data collection, in a university hospital in São Paulo. METHODS: Seventy-nine female patients who underwent routine mammography between 1998 and 2004 were studied. Lesions classified by the Breast Imaging Reporting and Data System (BI-RADS) as 4 or 5 underwent percutaneous biopsy using a large-core needle. Ninety-eight lesions were studied anatomopathologically. Paraffin blocks properly representing the lesions were selected for immunohistochemical analyses using the streptavidin-biotin-peroxidase technique with monoclonal mouse c-myc antibodies. RESULTS: Among the 98 lesions, 29 (29.6 percent) contained malignant neoplasia; 40 (40.8 percent) had a positive immunohistochemical reaction for c-myc. When the groups were divided between lesions without atypias versus atypical lesions plus malignant lesions, 31.03 percent of the 58 lesions without atypias were positive for c-myc and 55 percent of the 40 malignant and atypical lesions (P = 0.018). Comparing the atypical lesions with ductal carcinoma in situ versus the benign lesions without atypias, c-myc was present in 51.61 percent of the 31 atypical lesions and 31.03 percent of the benign lesions without atypias (P = 0.057). CONCLUSION: C-myc protein was more frequently expressed in atypical and malignant lesions than in benign lesions without atypias. C-myc expression correlated with the presence of atypias (P = 0.018).

CONTEXTO E OBJETIVO: Alterações nos genes reguladores da proliferação celular foram descritas em lesões pré-malignas. Os objetivos foram avaliar a expressão da proteína c-myc em biópsias de lesões mamárias não-palpáveis associadas a microcalcificações detectadas em mamografias de rastreamento e comparar estes resultados com as variáveis histopatológicas, clínicas e epidemiológicas. DESENHO E LOCAL: Estudo retrospectivo, em um hospital universitário em São Paulo. MÉTODOS: Setenta e nove pacientes do sexo feminino submetidas a mamografia de rotina de 1998 a 2004 foram estudadas. As lesões classificadas pelo sistema BI-RADS (Breast Imaging Reporting and Data) como 4 e 5 sofreram biópsias percutâneas com agulha grossa. Do ponto de vista anatomopatológico, foram estudadas 98 lesões. Os blocos com representação adequada para estudo imunoistoquímico com a técnica da estreptoavidina-biotina-peroxidase com o anticorpo monoclonal de camundongo c-myc foram incluídos. RESULTADOS: Das 98 lesões, 29 (29,6 por cento), continham neoplasia maligna; 40 (40,8 por cento) tiveram reação de imunoistoquímica positiva para o c-myc. Quando divididos os grupos em lesões sem atipia versus lesões atípicas mais lesões malignas, encontramos o c-myc positivo em 31,03 por cento das 58 lesões sem atipias e 55 por cento das 40 lesões atípicas e malignas (P = 0,018). Quando agrupamos as lesões atípicas com o carcinoma ductal in situ (CDIS) versus as lesões benignas sem atipias, observamos a presença do c-myc em 51,61 por cento das 31 lesões atípicas e 31,03 por cento das lesões benignas sem atipias (P = 0,057). CONCLUSÃO: A proteína c-myc está mais frequentemente expressa em lesões atípicas e malignas do que em lesões benignas sem atipia. A expressão do c-myc está correlacionada com a presença de atipia (P = 0,018).

DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis

Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchicalclustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%),followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.

Focos de criptas aberrantes el comienzo de la historia / Aberrant crypts foci, the begining of the tale

Aberrant crypts foci (ACF) are lesions characterized morphologically by abnormal crypts on the surface of the colonic mucosa and since its first description in rats, there has been several lines of evidence that ACF could be a precursor of colorectal cancer. The prevalence of ACF has been estimated in 53,6 per cent in normal people older than 50 years, 90 percent in patients with adenomas an 100 percent in patients with colorectal cancer. ACF are detected most commonly in distal colon and rectum, and these lesions have variable histological findings. There are several genetic abnormalities identified in ACF, and the earliest is the mutation of the gene K-ras. The ACF can be identified in vivo with magnificated endoscopy, methylene blue staining and chromoendoscopy, which allow their use as a marker for colorectal carcinogenesis and even predict the population risks, the individuals that are susceptible to receive chemoprevention and to establish surveillance strategies in colorectal cancer.

Focos de criptas aberrantes (FCA) constituyen lesiones caracterizadas por criptas morfológicamente anormales en la superficie de la mucosa colónica y desde su primera descripción en ratas, ha habido varias líneas de evidencia que sugieren que FCA podrían constituir un precursor de cáncer colorectal (CCR). La prevalencia de FCA ha sido estimada en 53,6 por ciento en sujetos normales mayores de 50 años, 90 por ciento en pacientes con adenoma y 100 por ciento en pacientes con CCR. Los FCA son detectados más comúnmente en colon distal y recto, y desde el punto de vista histológico estas lesiones tienen hallazgos variables. Existen múltiples alteraciones genéticas identificadas en FCA, siendo la más precoz la mutación del gene K-RAS. Los FCA puede ser identificados in vivo con endoscopía con magnificación, tinción de azul de metileno y cromoendoscopía, lo que permite su utilización como marcador para carcinogénesis colorectal y así predecir la población o individuos en riesgo, los que pueden ser susceptibles de recibir quimioprevención y ser incorporados en programas de vigilancia de CCR.

Inestabilidad microsatelital en lesiones preneoplásicas y neoplásicas del cuello uterino: Correlación con el genotipo del virus papiloma humano / Microsatellite instability and human papilloma virus genotypes in preneoplastic and neoplastic uterine cervix lesions

Background: The association between some specific human papilloma virus (HPV) types and cervix cancer is well known. However, the genetic conditions that favor the development of cervical cancer are less well known. Aim: To determine the presence of satellite instability (MSI) in preneoplastic and neoplastic lesions of the cervix and correlate these findings with HPV genotypes. Material and methods: Biopsy samples of cervical lesions were studied. Sixteen had low grade lesions, 22 had high grade lesions and 28 had an epidermoid cancer. Viral types were identified with polymerase chain reaction, dot-blot hybridization and restriction fragment length polymorphism. MSI was determined using a panel of eight highly informative microsatellites. Results: Microsatellite instability in at least one locus was observed in 91, 56 and 69 percent of low grade lesions, high grade lesions and epidermoid carcinomas, respectively. MSI-High grade, MSI-Low grade instability and microsatellite stability were observed in 5, 60 and 46 percent of samples, respectively. Two of three samples with high grade instability had HPV 52 genotype. Other viral subtypes had frequencies that ranged from 78 percent to 100 percent, with the exception of HPV16 that was present in only 53 percent of samples with low grade instability. Conclusions: Two thirds of biopsy samples from cervical lesions had MSI, mechanism that can be involved in the first stages of cervical carcinogenesis. The low frequency of high grade instability, its association with HPV52 and the low frequency of HPV16 in samples with low grade instability, suggest different coadjutant mechanisms in cervical carcinogenesis

Mecanismo de infección y transformación neoplásica producido por virus papiloma humano en el epitelio cervical / Infection mechanism and neoplastic transformation produced by human papilloma virus in cervical epithelium

Se presenta una revisión bibliográfica del mecanismo de infección y transformación neoplásica producida por el virus papiloma humano, de alto riesgo oncogénico, en el epitelio cervical. Se expone la interacción cápside receptor, internalización celular, expresión de genes tempranos, integración del genoma viral al de la célula huésped y algunos mecanismos vinculados a la proliferación y desarrollo neoplásico.

Promoter Methylation of E-cadherin in Hepatocellular Carcinomas and Dysplastic Nodules

In order to clarify the significance of E-cadherin methylation in multistep hepatocarcinogenesis, we examined the methylation status of the E-cadherin promoter region, using methylation-specific polymerase chain reaction in 64 hepatocellular carcinomas (HCCs) and 13 dysplastic nodules (DNs), and correlated these results with E-cadherin protein expression and clinicopathologic factors of HCCs. Promoter methylation was detected in 1 of 13 (7.7%) DNs, in 5 of 13 (38.5%) Edmondson and Steiner grade I HCCs, and in 27 of 51 (52.9%) grade II or III HCCs, and a significant correlation was observed between the methylation status and the stepwise progression of hepatocarcinogenesis (p=0.004). Reduced E-cadherin immunoreactivity was found in 18 of 64 (28%) HCCs, but in none of DNs. E-cadherin methylation status in HCCs was significantly correlated with microvascular invasion (p=0.02) and tumor recurrence (p=0.04), but not with reduced E-cadherin immunoreactivity. The Kaplan-Meier method showed that methylation status did not have a significant influence on the recurrence-free survival of HCC patients (p=0.15). Our results indicate that methylation of the E-cadherin promoter region is a frequent event in HCC, which may play an important role in the stepwise progression of hepatocarcinogenesis. And the promoter methylation of E-cadherin in HCC was found to be significantly correlated with microvascular invasion and recurrence.

Epstein-Barr Virus and p16INK4A Methylation in Squamous Cell Carcinoma and Precancerous Lesions of the Cervix Uteri

Methylation of p16 is an important mechanism in cervical carcinogenesis. However, the relationship between cervical squamous cell carcinoma (SCC) and Epstein-Barr virus (EBV) remains controversial. Here, we explored whether EBV infection and/or p16 gene inactivation would play any role in cervical carcinogenesis. Eighty-two specimens included 41 invasive SCCs, 30 cervical intraepithelial neoplasm (CIN; CIN 1, 11 cases, CIN II, 3 cases, CIN III 16 cases) and 11 nonneoplastic cervices. EBV was detected by polymerase chain reaction (PCR) for EBNA-1 and in situ hybridization for EBER-1. The p16 methylation-status and the expression of p16 protein were studied by methylation-specific PCR and immunohistochemistry, respectively. The materials were divided into four groups: 1) nonneoplastic cervices, 2) CIN I, 3) CIN II-III and 4) invasive SCCs. p16 methylation and p16 immunoexpressions increased in CIN and invasive SCCs than nonneoplastic tissue. p16-methylation and p16-immunoreactivities were higher in the EBV-positive group (p=0.009, p<0.001) than in the EBV-negative group. EBV was detected more frequently in CIN and SCCs than nonneoplastic cervices. In conclusion, a correlation between p16 methylation, p16 immunoreactivity and the detection of EBV strongly suggested that the cooperation of EBV and p16 gene may play a synergic effect on cell cycle deregulation.

Alteraciones genéticas en gastritis crónica: Estudio de inestabilidad microsatelital y pérdida de la heterocigocidad / Genetic changes in chronic gastritis: study of microsatellite instability and loss of heterozygosity

Background: Multifocal chronic gastritis, associated to intestinal metaplasia, is considered a preneoplastic lesion, closely associated to intestinal type gastric cancer. Aim: To study the frequency of microsatellite instability (MSI) and loss of heterozygosity (LOH) in areas of chronic gastritis and intestinal metaplasia in gastric biopsies of patients without cancer. Material and methods: Gastric biopsy samples from 34 patients without cancer (22 with multifocal atrophic gastritis and 12 with diffuse antral gastritis), were studied. Glands from areas of chonic gastritis and intestinal metaplasia and lymphocytes, were collected using laser microdissection of paraffin embedded samples. The analysis of 15 mono and dinucleotide microsatellites was used to assess LOH and MSI. Results: LOH and MSI were found in some of the markers in 55% (12/22) and 59% (13/22) of cases with intestinal metaplasia, respectively. Only one of 12 areas with diffuse atrophic gastritis had MSI and a different area had LOH (p <0.05 or less, when compared with areas of multifocal atrophic gastritis). Three areas of normal epithelium in patients with multifocal atrophic gastritis, also had alterations. Most of these alterations were concordant with adjacent areas with intestinal metaplasia. Conclusions: LOH and MSI was found in areas of intestinal metaplasia in more than half of the studied cases and in few areas of atrophic gastritis without intestinal metaplasia. These findings suggest that genotypic alterations may precede phenotypic modifications and that intestinal metaplasia is a preneoplastic lesion (Rev Méd Chile 2003; 131: 1365-74).

Síndrome de Peutz-Jeghers: predisposição a neoplasias e suas correlações clínico-genéticas / Peutz-Jeghers Syndrome: neoplasies predisposition and genetic-clinicals correlations

A síndrome de Peutz-Jeghers (SPJ) foi a primeira enfermidade identificada com suscetibilidade para o desenvolvimento de câncer associado à condição genética. Descrevem-se os avanços no diagnóstico, sua clínica, bem como sua correlação oncológica e genética.