RESUMO
BACKGROUND: Though there is considerable evidence that sphingosine kinase 1(SPHK1) plays a key role in hepatocellular carcinoma(HCC) progression, the prognostic value of SPHK1 expression in HCC with portal vein tumor thrombus (PVTT) remains unclear. Aims. The purpose of this study was to investigate the relationship of SPHK1 expression with PVTT and HCC recurrence after hepatectomy. METHODS: After screening of gene expression profiling of tumor cell lines, real-time PCR and immunohistochemistry were used to investigate the SPHK1 expression in PVTT and HCC samples. The clinical data of 199 HCC patients with nonmain PVTT who underwent liver resection with curative intention were studied. RESULTS: We identified SPHK1 as the most over-expressed gene in PVTT via gene expression profiling of one human PVTT cell line (CSQT-2). SPHK1 expression was an independent factor affecting survival (hazard ratio [HR] 1.799, 95% confidence interval [CI] 1.337-2.368, P < 0.001) and tumor recurrence (HR 1.451, 95% CI 1.087-1.935, P = 0.011). Patients with SPHK1 over-expression had a poorer prognosis than those with SPHK1 under-expression (P < 0.001 and P = 0.011 for survival and tumor recurrence). CONCLUSIONS: SPHK1 might represent a novel and useful prognostic marker of HCC progression in patients with PVTT.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Veia Porta , Trombose Venosa/enzimologia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Progressão da Doença , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Veia Porta/patologia , Veia Porta/cirurgia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Transdução de Sinais , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Trombose Venosa/etiologia , Trombose Venosa/genética , Trombose Venosa/mortalidade , Trombose Venosa/cirurgiaRESUMO
We aimed to study patients with splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT) searching for JAK2 mutations. We evaluated 14 patients (median age: 41.5 years) with portal vein thrombosis (PVT) = 7; mesenteric vein thrombosis (MVT) = 3; and CVT = 4. JAK2 V617F was assessed by allele specific PCR of peripheral blood DNA. In addition, DNA was sequenced for other JAK2 mutations. Other inherited and acquired thrombophilia risk factors were evaluated. JAK2 V617F was positive in four out of seven patients with PVT and in one CVT patient. These five patients had a diagnosis of myelo-proliferative disorder (MPD) at the moment of the occurrence of thrombosis (n = 2) or later (n = 2). Patients with MVT and CVT were negative for JAK2 V617F, except one patient with CVT and a diagnosis of essential thrombocythemia. No other JAK2 mutations were found in this cohort. Besides MPD, other thrombophilia risk factors were identified in five patients. One patient had MPD as well as thrombophilia risk factor. In this group, 4 out of 7 of the patients with PVT carried the JAK2 V617F mutation with or without overt MPD. However, the investigation of other JAK2 mutations may not be necessary in patients with thrombosis at unusual sites.
Assuntos
Trombose Intracraniana/genética , Janus Quinase 2/genética , Veias Mesentéricas , Mutação/genética , Veia Porta , Trombose Venosa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Trombose Intracraniana/enzimologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Trombose Venosa/enzimologiaRESUMO
We aimed to study patients with splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT) searching for JAK2 mutations. We evaluated 14 patients (median age: 41.5 years) with portal vein thrombosis (PVT) = 7; mesenteric vein thrombosis (MVT) = 3; and CVT = 4. JAK2 V617F was assessed by allele specific PCR of peripheral blood DNA. In addition, DNA was sequenced for other JAK2 mutations. Other inherited and acquired thrombophilia risk factors were evaluated. JAK2 V617F was positive in four out of seven patients with PVT and in one CVT patient. These five patients had a diagnosis of myeloproliferative disorder (MPD) at the moment of the occurrence of thrombosis (n = 2) or later (n = 2). Patients with MVT and CVT were negative for JAK2 V617F, except one patient with CVT and a diagnosis of essential thrombocythemia. No other JAK2 mutations were found in this cohort. Besides MPD, other thrombophilia risk factors were identified in five patients. One patient had MPD as well as thrombophilia risk factor. In this group, 4 out of 7 of the patients with PVT carried the JAK2 V617F mutation with or without overt MPD. However, the investigation of other JAK2 mutations may not be necessary in patients with thrombosis at unusual sites.
Nuestro objetivo fue estudiar pacientes con trombosis de las venas esplácnicas (TVE) o trombosis de las venas cerebrales (TVC) en búsqueda de mutaciones del gen quinasa Janus 2 (JAK2). Se estudiaron 14 pacientes (media de edad: 41.5 años) con trombosis de la vena porta (TVP n = 7), trombosis de la vena mesentérica (TVM, n = 3) y TVC (n = 4). La mutación V617F del gen JAK2 fue evaluada por reacción en cadena de la polimerasa (PCR) alelo-específica en muestras de sangre periférica. Además, se realizó secuenciación de ADN en búsqueda de otras mutaciones del gen JAK2 distintas de V617F. También se investigaron factores genéticos y adquiridos para trombofilia. JAK2 V617F fue positiva en 4 de 7 pacientes con TVP y en un paciente con TVC. Estos 5 pacientes con la mutación tuvieron diagnóstico de síndrome mieloproliferativo (SMP) en el momento de la detección de la trombosis (n = 2) o después (n = 3). Un paciente con TVP sufrió el episodio trombótico 18 años después del diagnóstico del SMP y la mutación JAK2 V617F fue negativa. No se encontraron otras mutaciones del gen JAK2 en este grupo d e pacientes. Además del diagnóstico de SMP, se identificaron otros factores de riesgo para trombofilia en 4 pacientes. Un paciente tuvo un factor de riesgo para trombofilia además del diagnóstico de SMP. La mutación JAK2 V617F se presentó en 4/7 de los pacientes con TVP con o sin un diagnóstico obvio de SMP. La investigación de otras mutaciones podría no ser necesaria en pacientes con trombosis en sitios poco frecuentes.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose Intracraniana/genética , /genética , Veias Mesentéricas , Mutação/genética , Veia Porta , Trombose Venosa/genética , Trombose Intracraniana/enzimologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Trombose Venosa/enzimologiaRESUMO
BACKGROUND: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed. AIM: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses. METHODS: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104). RESULTS: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up. CONCLUSIONS: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.
Assuntos
Síndrome de Budd-Chiari/genética , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Veia Porta , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Brasil , Síndrome de Budd-Chiari/diagnóstico , Síndrome de Budd-Chiari/enzimologia , Síndrome de Budd-Chiari/fisiopatologia , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/fisiopatologia , Fenótipo , Veia Porta/fisiopatologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Circulação Esplâncnica/genética , Fatores de Tempo , Trombose Venosa/diagnóstico , Trombose Venosa/enzimologia , Trombose Venosa/fisiopatologia , Adulto JovemRESUMO
Introducción: Diversos estudios han relacionado diferentes factores trombofílicos al desarrollo de trombosis venosa profunda (TVP). Entre las alteraciones adquiridas y hereditarias asociadas a trombofilias destacan las relacionadas al metabolismo de la homocisteína. Sin embargo, los resultados observados son contradictorios e influenciados por diversos factores, entre ellos la etnia. Objetivo: Considerando la escasa información sobre las bases genéticas de la TVP en Chile, el objetivo del presente estudio fue investigar la posible asociación entre la mutación C677T del gen de la metilentetrahidrofolato reductasa (MTHFR) y TVP en individuos de nuestra región. Métodos: Fueron evaluados 60 pacientes con TVP (17 a 87 años) y 120 controles (21 a 81 años), de ambos sexos, todos provenientes a la IX Región de La Araucanía. La presencia de TVP fue confirmada mediante ecografía Doppler. La genotipificación de la mutación C677T fue realizada mediante la técnica de PCR-RFLP. Resultados: El genotipo homocigoto TT para la mutación C677T del gen MTHFR fue más frecuente en los individuos con TVP (28 por ciento vs. 15 por ciento, p=0.047). Similarmente, el alelo mutado 677T fue también más frecuente en los pacientes con TVP (0.53 vs. 0.39, p=0.018). La Odss ratio (OR) asociada a la variante 677T confirma la interacción encontrada(OR= 2.0, IC 95 por ciento 1.06 3.79, p<0.05). Conclusión: Los datos sugieren que la mutación C677T del gen MTHFR contribuye para el desarrollo de TVP en la población analizada. Sin embargo, hasta que más antecedentes sean reunidos, nosotros no recomendamos incluir la genotipificación de esta mutación en el screening de rutina de trombofilias.
Background: Several studies relate the presence of diverse thrombophilic factors to the development of deep venous thrombosis (DVT). Alteration of homocisteine metabolism has been associated to hereditary and acquired forms of thrombophilia. However, several factors may modify this relationship, among them the subjects ethnic origin. Aim: To investigate a possible association of the C677T mutation of metilentetrahydrofolate reductase (MTHFR) to DVT. Methods: Sixty patients with DVT, aged 17 to 87 years, and 120 control subjects (21 to 81 years old), males and females, all residents of the Araucania region were evaluated. DVT was confirmed by duplex ultrasonography. PCR-RFLP was used to determine de presence of the C677T mutation Results: The homozygous TT genotype for C677T was more frequent in DVT subjects (28 percent) as compared to controls (15 percent, p=0.047). The mutated alelle of C677T was also more frequent in the DVT group (53 percent vs 39 percent, p=0.018). The OR for DVT associated to C677T was 2.0 (95 percent CI 1.06 3.79, p<0.05) Conclusion: The data suggest that the C677T mutation of MTHFR is associated to DVT. However, more information is needed before making a recommendation for use of gene characterization of this mutation in screening for thrombophilia.