RESUMO
The Wnt/beta-catenin signalling pathway is activated in many human hepatocellular carcinomas (HCC). Identification of beta-catenin mutation relies mostly on sequence analysis and/or immunohistochemistry. beta-catenin mutation may also be detected by analysing the expression of its target genes. The GLUL gene encoding glutamine synthetase (GS), for example, appears to be a pertinent marker. The aim of this study was to correlate GS immunostaining and beta-catenin mutations with clinicopathological features in HCC. We found that GS immunostaining had a sensitivity of 90% for the detection of beta-catenin mutations, with 98% specificity, whereas beta-catenin immunostaining had a sensitivity of 63% with 98% specificity. We used the sensitive GS marker to characterize 190 HCC cases. Sixty-eight (36%) cases displayed Wnt/beta-catenin activation. In addition to their well-differentiated pattern, these tumours exhibited significant features such as a homogeneous microtrabeculo-acinar pattern, low-grade cellular atypia, and cholestasis. As these tumours exhibited cholestasis, we hypothesized that beta-catenin acts on specific bile synthesis and/or transport pathways. In conclusion, we propose that GS immunostaining and a cholestatic pattern are relevant criteria for the identification of HCC with beta-catenin mutations.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Colestase/patologia , Glutamato-Amônia Ligase/análise , Neoplasias Hepáticas/patologia , beta Catenina/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Distribuição de Qui-Quadrado , Colestase/genética , Colestase/metabolismo , Análise Mutacional de DNA , Expressão Gênica , Glutamato-Amônia Ligase/genética , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Transdução de Sinais , Proteína Wnt1/metabolismo , beta Catenina/análise , beta Catenina/metabolismoRESUMO
Aurora-A, a member of serine/threonine kinase, is implied in mitosis and centrosome maturation. Increasing levels of Aurora-A have been shown to be present in several malignancies and especially in bladder cancer. No immunohistochemical marker has shown to be able to predict the clinical outcome of patients with superficial bladder cancer, except MIB-1, as a predictive marker of relapse and progression. The aim was to investigate the expression of Aurora-A and MIB-1 in tissue micro arrays of superficial bladder cancer representative of pTa papillary urothelial neoplasm with different degrees of aggressiveness (low malignant potential [PUNLMP], non-invasive papillary urothelial carcinoma low grade [NILGC], non-invasive papillary urothelial carcinoma high grade [NIHGC] and carcinoma in situ). We analysed predictive values of both markers, their specificity and sensitivity in tumor recurrence. Aurora-A was a sensitive marker to predict tumor recurrence especially for pTa (PUNLMP, NILGC; PUNLMP p<0.001, NILGC p<0.001) with statistical significant correlation between immunohistochemical staining and clinical outcome. MIB-1 expression displayed statistical difference p=0.002 in the PUNLMP group and p=0.03 in the NILGC group. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. The combination of both markers seems to have a very powerful predictive value of recurrence (p<0.001).