The ERBB2 gene polymorphisms rs2643194, rs2934971, and rs1058808 are associated with increased risk of gastric cancer

Gastric cancer (GC) is the third most lethal type of cancer worldwide. Single nucleotide polymorphisms (SNPs) in regulatory sites or coding regions can modify the expression of genes involved in gastric carcinogenesis, as ERBB2, which encodes for the tyrosine-kinase receptor HER-2. The aim of this work was to analyze the association of the polymorphisms: rs2643194, rs2517951, rs2643195, rs2934971, and rs1058808 with GC, as they have not yet been analyzed in GC patients, as well as to report their frequency in the general Mexican population (GMP). We studied genomic DNA from subjects with GC (n=74), gastric inflammatory diseases (GID, n=76 control subjects), and GMP (n=102). Genotypes were obtained by means of real-time PCR and DNA-sequencing. The risks for GC were estimated through odds ratio (OR) using the Cochran-Armitage trend test and multinomial logistic regression. Increased risk for GC was observed under the dominant inheritance model for the rs2643194 TT or CT genotypes with an OR of 2.75 (95%CI 1.12−6.75, P=0.023); the rs2934971 TT or GT genotypes with an OR of 2.41 (95%CI 1.01−5.76, P=0.043), and the rs1058808 GG or CG genotypes with an OR of 2.21 (95%CI 1.00−4.87, P=0.046). The SNPs rs2643194, rs2934971, and rs1058808 of the ERBB2 gene were associated with increased risk for GC.

Hormone Receptor-negative Metastatic Breast Cancer Presented as Cancer from an Unknown Primary Site / 대한내과학회지

A 37-year-old woman was admitted to our hospital because of cervical and axillary lymphadenopathy that developed after delivery. An axillary lymph node biopsy revealed metastatic adenocarcinoma. Immunohistochemical staining indicated that the tumor cells expressed c-ErbB-2, but were negative for the estrogen and progesterone receptors. No definite evidence of breast cancer was detected. The patient underwent chemotherapy for suspected metastatic breast cancer. She complained of swelling in the left breast 22 months later, and a biopsy showed invasive ductal carcinoma. Here, we report a case of hormone receptor-negative occult breast cancer in a patient with cervical and axillary lymphadenopathy presenting as a cancer with an unknown primary site.

Instabilidade genômica em neoplasias malignas da mama em função da concentração de alumínio intracelular / Genomic instability association with intracellular aluminum concentration in breast tumors

Introdução: A hipótese de que os efeitos do alumínio em células humanas podem ter implicações clínicas tem sido levantada há algum tempo, especialmente no que concerne ao câncer de mama. As evidências laboratoriais mostrando altos níveis de alumínio nos tecidos da mama e os efeitos biológicos conhecidos sobre esse metal não são suficientes para estabelecer uma relação causal entre a exposição ao alumínio e o risco aumentando para o desenvolvimento do câncer de mama. O objetivo deste estudo foi estabelecer a concentração de alumínio nas áreas centrais e periféricas de tumores de mama, assim como na área glandular normal da mama e correlacionar esses achados com a instabilidade dos genes ERBB2, C-MYC e CCND1 e a aneuploidia dos cromossomos que contêm estes genes. Métodos: Para este estudo foram incluídas 176 mulheres com diagnóstico de carcinoma invasor de mama, com tumores maiores de 1cm3, sem quimioterapia neoadjuvante, operadas enter 2008 e 2010 no Hospital da Mulher Prof. Dr. José Aristodemo Pinotti - Centro de Atenção Integral à Saúde da Mulher (CAISM) - UNICAMP. Para a análise da concentração de alumínio intracelular, amostras de 150 pacientes foram consideradas viáveis; para a análise da instabilidade genômica em função da concentração de alumínio, 118 amostras foram consideradas viáveis, definindo o espaço amostral de cada um dos artigos apresentados. As amostras das áreas centrais e periféricas dos tumores de mama e das áreas glandulares normais da mama foram obtidas. A quantificação do alumínio contido nos tecidos da mama foi feita através da técnica de Espectrometria de Absorção Atômica em Forno de Grafite (GFAAS). Uma lâmina de Tissue Microarray (TMA), contendo as amostras de tumor e tecido normal foi utilizado para a realização da técnica de FISH para acessar o status dos genes ERBB2, C-MYC e CCND1 e dos centrômeros dos seus respectivos cromossomos 17, 8 e 11. Os dados clínico-patológicos foram obtidos dos prontuários de pacientes...

Introduction: It has long been hypothesized if the effects of aluminum on human cells may have clinical implications, especially regarding to breast cancer. The current laboratorial evidence showing higher levels of aluminum in breast tissues and the known biological effects of this metal, are not sufficient to establish a causal relationship between aluminum exposure and increased risk of developing breast cancer. The objective of this study was to establish the aluminum concentration in the central and peripheral areas of breast tumors as well as in normal glandular area of the breast and to correlate these findings with the instability of ERBB2, C-MYC and CCND1, and aneuploidy of chromosomes harboring these genes. Methods: This study included 176 women diagnosed with invasive breast carcinoma with tumors larger than 1cm3 without neoadjuvant chemotherapy, operated between 2008 and 2010 at the Women's Hospital Professor. Dr. José Aristodemo Pinotti - Centro de Atenção Integral à Saúde da Mulher (CAISM) - UNICAMP. To analyze the intracellular concentration of aluminum, samples from 150 patients were considered viable; for the analysis of genomic instability as a function of the concentration of aluminum, 118 samples were considered viable. These figures define the sample of each of the two articles that this PhD thesis comprises. Evaluation of tissue aluminum content was carried out using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). A TMA slide containing the tumor and normal samples was used in FISH assays to assess ERBB2, C-MYC and CCND1 and the respective chromosomes 17, 8 and 11 centromeres status. Clinicopathological data were obtained from patients' records. Results: The average aluminum content found in breast was 1.88 mg/kg in the central tumor areas, 2.10 mg/ kg in the peripheral tumor areas and 1.68 mg/ kg in the normal tissue areas...

A method for detection of HER2 gene amplification in breast cancer tissues: Chromogenic in situ hybridization method and its modification / 第二军医大学学报

Objective: To apply chromogenic in situ hybridization (CISH for detection of HER2 gene amplification in breast cancer tissues and to discuss some modifications of the CISH method. Methods: HER2 gene amplification was detected by CISH in 60 breast cancer specimens with an immunohistochemical score over 2+. The correlation between the results of IHC and CISH was analyzed. Our experience in CISH manipulation was summarized and optimization to CISH was discussed. Results: CISH identified gene amplification in 91% (40/44) specimens with an IHC score of 3+ and in 50% (8/16) specimens with an IHC score of 2+. The total concordance rate between IHC and CISH was 80% (48/60, P<0.01). The thickness of sections should be controlled within 4-5 μm; the denaturation should be complete; and the post-hybridization washing temperature and time were also very important and the temperature should be controlled at 70-75 °C. The dyeing time of hematoxylin should also be restrictedly controlled. Positive control should be set up in the experiment for high quality of the experiment. Conclusion: CISH has high concordance rate with IHC in examining HER2 amplification and it may be a new method for detection of HER2 gene. The thickness of the sections, the post hybridization washing temperature and time, and the time of hematoxylin dyeing should be strictly controlled.

Clinical Significance of p53, c-erbB-2, Chromogranin A and PCNA in the Ampullary Carcinoma / 대한암학회지

PURPOSE: To determine the clinical significance of p53, c-erbB-2, chromogranin A (CgA), proliferating cell nuclear antigen (PCNA) expression in ampullary carcinoma, a retrospective study was performed. MATERIALS AND METHODS: The cases of 96 patients who underwent curative resection for ampullary carcinoma during the ten-year period (1986-95) were reviewed. And, using paraffin-embedded tumor tissues, immunohistochemical (IHC) staining for p53, c-erbB-2, CgA, and PCNA was performed. RESULTS: The overall five-year survival rate (5-YSR) for these 96 patients was 58%. With regard to TNM stage, the 5-YSR was 71% for stage I (n=36), 62% for stage II (n=29), and 39% for stage III (n=31), respectively. IHC expression rate was 17.6% for c-erbB-2, 19.2% for CgA, and 42.9% for p53. The relative proportion of labelling index of PCNA (50%) was 30.8%, 25.3%, and 44.0%, respectively. The PCNA labelling index showedsignificant correlation with tumor size (p=0.032). The PCNA labelling index, c-erbB-2, CgA and p53 were not correlated to extent of invasion, lymph node metastasis, stage, or histologic type. CgA and c-erbB-2 expression and the PCNA labelling index thus had no prognostic value. With regard to p53, the 5-YSR of p53 negative cases was 68.6%; that of p53 positive cases was 47%, with significant difference (p=0.038). CONCLUSION: This result suggests that p53 expression is related to poor prognosis of ampullary carcinoma, and that c-erbB-2 and CgA expression, and the PCNA labelling index, are not significant prognostic factors.

A method for detection of HER2 gene amplification in breast cancer tissues:chromogenic in situ hybridization method and its modification / 第二军医大学学报

Objective:To apply chromogenic in situ hybridization(CISH)for detection of HER2 gene amplification in breast cancer tissues and to discuss some modifications of the CISH method.Methods:HER2 gene amplification was detected by CISH in 60 breast cancer specimens with an immunohistochemical score over 2+.The correlation between the results of IHC and CISH was analyzed.Our experience in CISH manipulation was summarized and optimization to CISH was discussed.Results:CISH identified gene amplification in 91%(40/44)specimens with an IHC score of 3+ and in 50%(8/16)specimens with an IHC score of 2+.The total concordance rate between IHC and CISH was 80%(48/60,P