Prognostic and Predictive Significance of MYC and KRAS Alterations in Breast Cancer from Women Treated with Neoadjuvant Chemotherapy

Breast cancer is a complex disease, with heterogeneous clinical evolution. Several analyses have been performed to identify the risk factors for breast cancer progression and the patients who respond best to a specific treatment. We aimed to evaluate whether the hormone receptor expression, HER2 and MYC genes and their protein status, and KRAS codon 12 mutations may be prognostic or predictive biomarkers of breast cancer. Protein, gene and mutation status were concomitantly evaluated in 116 breast tumors from women who underwent neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide. We observed that MYC expression was associated with luminal B and HER2 overexpression phenotypes compared to luminal A (p= 2.5 was a protective factor for chemotherapy resistance. On the other hand, age and grade 2 tumors were a risk factor. Additionally, luminal B, HER2 overexpression, and triple-negative tumors presented increased odds of being resistant to chemotherapy relative to luminal A tumors. Thus, breast tumors with KRAS codon 12 mutations seem to present a worse prognosis. Additionally, MYC amplification may help in the identification of tumors that are sensitive to doxorubicin plus cyclophosphamide treatment. If confirmed in a large set of samples, these markers may be useful for clinical stratification and prognosis.Fundacao Amazonia Paraense de Amparo a PesquisaConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Ophir Loyola Hosp, Mastol Unit, Belem, PA, BrazilUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilFed Univ Para, Inst Biol Sci, Human Cytogenet Lab, BR-66059 Belem, PA, BrazilHosp Univ La Paz, Res Unit Unidad Invest, Madrid, SpainFed Univ Para, Nucleu Res Oncol, Joao de Barros Barreto Univ Hosp, BR-66059 Belem, PA, BrazilUniv Fed Piaui, Dept Biomed, Parnaiba, PI, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, São Paulo, BrazilFundacao Amazonia Paraense de Amparo a Pesquisa: FAPESPA/PPSUS 247/2009Fundacao Amazonia Paraense de Amparo a Pesquisa: 300240/2009Web of Scienc

Occurrence of Helicobacter pylori and Epstein-Barr virus infection in endoscopic and gastric cancer patients from Northern Brazil

Background: Helicobacter pylori (HP) and Epstein-Barr virus (EBV) have been associated with cancer development. We evaluated the prevalence of HP, HP CagA(+) and EBV infection in gastric cancer (GC) samples from adults and in gastric tissues from patients who underwent upper endoscopy (UE).Methods: Samples from UE and GC were collected to investigate the presence of HP infection and the HP virulence factor CagA by a urease test and PCR. the presence of EBV was detected by Eber-1 in situ hybridization.Results: in UE, 85.5% of juvenile patients showed some degree of gastritis (45.3% of patients with mild gastritis and 54.7% with moderate/severe gastritis) and patients with mild gastritis were younger than patients with moderate/severe gastritis. Among adults, 48.7% presented mild gastritis and 51.3% moderate/severe gastritis. HP infection was detected in 0% of normal mucosa, 58.5% of juvenile gastritis patients, 69.2% of adult gastritis patients and 88% of GC patients. in these same groups, HP CagA(+) was detected in 0%, 37.7%, 61.5% and 67.2% of tissue samples, respectively. in juvenile patients, HP infection was more common in those with gastritis than in normal samples (p = 0.004). the patients with either HP or HP CagA(+) were older than patients without these pathogens (p < 0.05). in juvenile patients, HP infection was more frequent in cases of moderate/severe gastritis than in cases of mild gastritis (p = 0.026). Moreover, in patients with GC, HP infection was more frequent in males than in females (p = 0.023). GC patients with HP CagA(+) were older than patients with HP CagA-(p = 0.027). HP CagA(+) was more common in intestinal-type than diffuse-type GC (p = 0.012). HP CagA(+) was also associated with lymph-node (p = 0.024) and distal (p = 0.005) metastasis. No association between EBV infection and HP infection or any clinicopathological variable was detected.Conclusions: Our results suggest that HP is involved in the pathophysiology of severe gastric lesions and in the development of GC, particularly when CagA(+) is present. EBV was not the primary pathogenic factor in our samples.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fed Univ Para, Inst Ciencias Biol, Lab Citogenet Humana, BR-66075110 Belem, PA, BrazilFed Univ Para, Inst Ciencias Saude, BR-66075110 Belem, PA, BrazilCtr Univ Para, Belem, PA, BrazilUniversidade Federal de São Paulo, Dept Ortopedia & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morfol & Genet, Disciplina Genet, São Paulo, BrazilFed Univ Para, BR-66075110 Belem, PA, BrazilUniv Fed Ceara, Fac Odontol, Dept Oral Pathol, Fortaleza, CE, BrazilUniversidade Federal de São Paulo, Dept Ortopedia & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morfol & Genet, Disciplina Genet, São Paulo, BrazilWeb of Scienc

MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer

BACKGROUND: \ud MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation.\ud METHODS: \ud We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines.\ud RESULTS: \ud MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells.\ud CONCLUSION: \ud In conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful indicator of poor prognosis. Furthermore, MYC is a candidate target for new therapies against gastric cancer.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Detection of Epstein-Barr virus in gastric adenocarcinoma: qPCR and fish comparison

Scientifc initiation scholarships were paid by National Council for Scientifc and Technological Development (CNPq). Salaries were paid by Evandro Chagas Institute (IEC) and Federal University of Pará. Equipment and supplies were provided by the IECMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilFederal University of Pará. Institute of Biological Sciences. Laboratory of Human Cytogenetics. Belém, PA, BrazilMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilMinistério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, BrasilFederal University of Pará. Institute of Biological Sciences. Laboratory of Human Cytogenetics. Belém, PA , Brazil / Ophir Loyola Hospital. Molecular Biology Laboratory. Belém, PA, BrazilEBV-associated gastric cancer accounts for about 10% of all gastric carcinomas worldwide. We aimed to verify the prevalence of EBV in gastric adenocarcinoma samples using FISH and qPCR and comparing the results obtained by both techniques. Gastric cancer samples from 191 cases were analyzed. The FISH assay was performed to detect small EBV RNAs (EBER1) and qPCR was performed to detect the EBV-EBNA-1 gene region. Cohen's kappa index and the chi-square test were used to compare the methodologies and investigate correlations with the clinical-pathological data of the gastric adenocarcinoma patients. Most of the patients were men, and the average age was 60 years. The intestinal subtype cancer presented more aggressive stages with 90% of patients having a reactive FISH for EBV (EBV+), although the virus infection frequency in epithelial gastric tissue was only 1%. No positive association with clinicopathological features and EBV+ was found by FISH. Using qPCR analysis, the percentage of positive samples was lower (52.4%), and a positive association was found in samples from older patients (> 60 years). Interestingly, 71 qPCR-negative cases were detected by FISH in the presence of non-epithelial cells and in 10 qPCR-positive cases with no evidence of EBV according to FISH. The concordance between the two techniques was low, with only 57.6%. FISH is more informative for associating the gastric carcinoma with EBV positivity in tumor/epithelial cells; however, qPCR can provide relevant information regarding the progression and characteristics of neoplasia

PD-L1 Expression Associated with Epstein—Barr Virus Status and Patients’ Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein–Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p &lt; 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p &lt; 0.0001). In the Kaplan–Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p &lt; 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine

hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions

Background: Gastric cancer is a serious public health problem in Northern Brazil and in the world due to its high incidence and mortality. Despite the severity of the disease, more research is needed to better understand the molecular events involved in this intestinal-type gastric carcinogenesis process. Since precancerous lesions precede intestinal-type gastric cancer, here, we evaluated the hTERT, MYC, and TP53 mRNA and protein expression, as well as TP33 copy number, in gastric preneoplastic lesions.Methods: We evaluated 19 superficial gastritis, 18 atrophic gastritis, and 18 intestinal metaplasia from cancer-free individuals of Northern Brazil. Quantitative reverse transcription PCR was used to analyze the mRNA expression and immunohistochemical methods were used to assess protein immunoreactivity in tissue samples. the number of TP53 gene copies was investigated in gastric diseases by quantitative PCR.Results: We observed hTERT, MYC, and p53 immunoreactivity only in intestinal metaplasia samples. the immunoreactivity of these proteins was strongly associated with each other. A significantly higher MYC mRNA expression was observed in intestinal metaplasia compared to gastritis samples. Loss of TP53 was also only detected in intestinal metaplasia specimens.Conclusions: We demonstrated that hTERT, MYC, and TP53 are deregulated in intestinal metaplasia of individuals from Northern Brazil and these alterations may facilitate tumor initiation

Clinicopathological features and protein expression by <i>HER2</i> and <i>MYC</i> amplification status.

*<p>Reference group for logistic regression analysis; ** Differentially expressed between groups, p<0.05. N: number of samples; OR: odds ratio; CI: confidence interval. HR: hormone receptor; CEP17: chromosome 17 signals ; CEP8: chromosome 8 signals; pol8: chromosome 8 polysomy.</p