Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.
DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively (χ(2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis.
Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.
Introdução: Os inibidores das proteínas de checkpoint (IC), sobretudo os anti-PD-1, anti-PD-L1 e anti-CTLA-4, têm sido cada vez mais utilizados na terapia contra o câncer. Em comparação com a terapêutica quimioterápica convencional, os ICs têm um perfil de toxicidade diferente, especialmente a ocorrência de efeitos adversos imunomediados (EAim) contra múltiplos sistemas, incluindo glândulas endócrinas. A compreensão dos eventos adversos relacionados ao tratamento dessas drogas é fundamental para a prática clínica e se detectados de modo precoce, podem ser reversíveis. Objetivos: O objetivo deste estudo foi descrever a incidência das principais disfunções tireoidianas secundárias ao tratamento com IC em um grupo de pacientes oncológicos em vigência de tratamento imunoterápico para diversos tipos de cânceres. Métodos: Estudo retrospectivo de pacientes diagnosticados com diferentes tipos de cânceres, submetidos a terapêutica com IC, entre fevereiro de 2015 a fevereiro de 2019, acompanhados no Centro de Oncologia Clínica do Hospital Sírio Libanês, unidade Brasília. Avaliou-se a função tireoidiana destes pacientes, através de dosagens hormonais de TSH e T4 livre ao longo do tratamento, a fim de verificar o desenvolvimento de disfunção tireoidiana. Resultados: Um total de 45 pacientes foram analisados, sendo excluídos 19. Dentre os demais pacientes, a prevalência de alteração nos níveis de TSH ou T4L ao longo do tratamento com Nivolumabe, foi de 7 pacientes (58,33%), enquanto, apenas 5 (41,66%) usuários de Pembrolizumabe apresentaram alterações nos níveis dos hormônios tireoidianos, sendo o hipotireoidismo a alterações mais prevalente no estudo. Além disso, não houve associação entre o tipo tumoral e a incidência de disfunções tireoidianas induzidas pela IC. Conclusão: As reações adversas envolvem qualquer órgão/tecido, sendo a disfunção tireoidiana umas das endocrinopatias mais frequentes. A monitorização da função tireoidiana através das dosagens hormonais favorece o diagnóstico e o tratamento precoce, com possível reversão dos sintomas e maior tolerância do paciente ao tratamento. Na população avaliada, encontrou-se uma incidência elevada de disfunções hormonais tireoidianas neste tipo de tratamento. Apesar dos resultados obtidos, novas pesquisas são necessárias para melhor entendimento sobre o desenvolvimento de doenças endócrinas com terapias inibidoras das proteínas de checkpoint
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