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1.
Oral Oncol ; 83: 81-90, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30098783

RESUMEN

OBJECTIVES: To identify potential molecular drivers associated with prognosis and response to treatment in advanced oropharyngeal squamous cell carcinomas (OPSCC). MATERIALS AND METHODS: Thirty-three OPSCC biopsies from untreated Brazilian patients were evaluated for human papilloma virus genotyping, genome wide copy number alterations and gene expression profiling. Data were integrated using CONEXIC algorithm. Validation with TCGA dataset and confirmation by RT-qPCR of candidate genes were performed. RESULTS: High-risk HPV positive cases, detected in 55% of advanced OPSCC, were associated with better outcome. Losses of 8p11.23-p11.22, 14q11.1-q11.2 and 15q11.2, and gains of 11q13.2 and 11q13.2-q13.3 were detected as recurrent alterations. Gains of 3q26.31 and 11q13.2 and losses of 9p21.3 were exclusively detected in HPV-negative tumors. Two clusters of expression profiles were observed, being one composed mostly by HPV positive cases (83%). HPV-positive enriched cluster showed predominantly immune response-related pathways. Integrative analysis identified 10 modulators mapped in 11q13, which were frequently cancer-related. These 10 genes showed copy number gains, overexpression and an association with worse survival, further validated by TCGA database analyses. Overexpression of four genes (ORAOV1, CPT1A, SHANK2 and PPFIA1) evaluated by RT-qPCR confirmed their association with poor survival. Multivariate analysis showed that PPFIA1 overexpression and HPV status are independent prognostic markers. Moreover, SHANK2 overexpression was significantly associated with incomplete response to treatment. CONCLUSION: The integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.


Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Cromosomas Humanos Par 11 , Oncogenes , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/terapia , Resultado del Tratamiento , Proteínas Adaptadoras Transductoras de Señales/genética , Alphapapillomavirus/aislamiento & purificación , Carcinoma de Células Escamosas/virología , Mapeo Cromosómico , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Neoplasias Orofaríngeas/virología , Pronóstico , Transcriptoma
2.
Ann Oncol ; 25(1): 69-75, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24285016

RESUMEN

BACKGROUND: Ataxia telangiectasia-mutated (ATM) gene downexpression has been reported in sporadic breast carcinomas (BC); however, the prognostic value and mechanisms of ATM deregulation remain unclear. PATIENTS AND METHODS: ATM and miRNAs (miR-26a, miR-26b, miR-203, miR-421, miR-664, miR-576-5p and miR-18a) expression levels were evaluated by quantitative real-time PCR (RT-qPCR) in 52 BC and 3 normal breast samples. ATM protein expression was assessed by immunohistochemistry in 968 BC and 35 adjacent normal breast tissues. ATM copy number alteration was detected by array comparative genomic hybridization (aCGH) in 42 tumours. RESULTS: Low ATM levels were associated with tumour grade. Absence of ATM protein expression was associated with distant metastasis (P < 0.001), reduced disease-free survival (DFS, P < 0.001) and cancer-specific survival (CSS, P < 0.001). Multivariate analysis indicated ATM protein expression as an independent prognostic marker for DFS (P = 0.001, HR = 0.579) and CSS (P = 0.001, HR = 0.554). ATM copy number loss was detected in 12% of tumours and associated with lower mRNA levels. miR-421 over-expression was detected in 36.5% of cases which exhibit lower ATM transcript levels (P = 0.075, r = -0.249). CONCLUSIONS: The data suggest that ATM protein expression is an independent prognostic marker in sporadic BC. Gene copy number loss and miR-421 over-expression may be involved in ATM deregulation in BC.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Dosificación de Gen , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Clasificación del Tumor , Pronóstico , Modelos de Riesgos Proporcionales
3.
Ann Oncol ; 21(4): 734-740, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19914962

RESUMEN

BACKGROUND: The clinical relevance of transforming growth factor-beta (TGF-beta)-signalling pathway in breast carcinomas (BCs) remained elusive. This study aimed to evaluate the prognostic value of TGF-beta1 and transforming growth factor-beta type II receptor (TGF-betaRII) expression levels in tumour cells and their association with the established biomarkers in BC. PATIENTS AND METHODS: In 324 BC from patients with long-term follow-up, the TGF-beta1 and TGF-betaRII transcript and protein expression levels were assessed. RESULTS: TGF-beta1 and TGF-betaRII down-expression was significantly associated with BC. Negative TGF-beta1 and TGF-betaRII protein status was associated with the development of distant metastasis (P = 0.003 and P = 0.029, respectively). In multivariate analysis, TGF-beta1-positive tumours were associated with increased disease-free survival (DFS) [hazard ratio (HR) = 0.489, P = 0.003]. TGF-betaRII positivity was an independent prognostic factor for DFS (HR = 0.439, P = 0.001) and overall survival (OS) (HR = 0.409, P = 0.003) in human epidermal growth factor receptor-2 (HER2)-negative patients. Absence of TGF-beta1 and TGF-betaRII proteins in breast tumour cells was significantly associated with metastasis development. CONCLUSIONS: To the best of our knowledge, this is the first report indicating the relevance of HER2 status in discriminating TGF-betaRII as a prognostic marker for DFS and OS in human BC. These data indicate that TGF-betaRII protein analysis in tumour cells could be introduced in clinical practice as additional prognostic biomarker in HER2-negative BC.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Carcinoma/diagnóstico , Genes erbB-2 , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/mortalidad , Regulación hacia Abajo , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Análisis de Supervivencia , Factor de Crecimiento Transformador beta1/genética , Adulto Joven
4.
Microbes Infect ; 2(7): 745-51, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10955954

RESUMEN

An inflammatory dilated cardiomyopathy occurs in 30% of Chagas' disease patients, chronically infected by Trypanosoma cruzi, while the remaining infected individuals are asymptomatic. Studies have indicated a role for genetic factors in the susceptibility to Chagas' disease cardiomyopathy. In an attempt to identify the genetic factors influencing the development and outcome of Chagas' cardiomyopathy, we compared the frequencies of alleles from two candidate gene loci, class II HLA and a microsatellite marker for the human cardiac beta-myosin heavy chain gene in different clinical groups. Patients were grouped as asymptomatic or with severe or mild cardiomyopathy. The results indicate that the HLA and myosin microsatellite allele profiles in all cardiomyopathy and in asymptomatic groups are similar. In conclusion, these results establish that polymorphism of HLA-DR and -DQ molecules, as well as beta-cardiac myosin, do not influence the susceptibility to different clinical forms of Chagas' disease or the progression to severe Chagas' cardiomyopathy. On the other hand, male sex was identified as a risk factor for progression to the more severe forms of cardiomyopathy (relative risk = 8.75).


Asunto(s)
Cardiomiopatía Chagásica/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Cadenas Pesadas de Miosina/genética , Polimorfismo Genético , Adulto , Factores de Edad , Anciano , Cardiomiopatía Chagásica/diagnóstico por imagen , Cardiomiopatía Chagásica/epidemiología , ADN/análisis , ADN/sangre , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Fenotipo , Riesgo , Factores de Riesgo , Factores Sexuales , Ultrasonografía
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