Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs)

Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene, mainly at positions c.-124 and c.-146 bp, are frequent in several human cancers; yet its presence in gastrointestinal stromal tumor (GIST) has not been reported to date. Herein, we searched for the presence and clinicopathological association of TERT promoter mutations in genomic DNA from 130 bona fide GISTs. We found TERT promoter mutations in 3.8% (5/130) of GISTs. The c.-124C>T mutation was the most common event, present in 2.3% (3/130), and the c.-146C>T mutation in 1.5% (2/130) of GISTs. No significant association was observed between TERT promoter mutation and patient's clinicopathological features. The present study establishes the low frequency (4%) of TERT promoter mutations in GISTs. Further studies are required to confirm our findings and to elucidate the hypothetical biological and clinical impact of TERT promoter mutation in GIST pathogenesis.

Expressão de transtirretina no sistema gastrointestinal do murganho

A transtirretina (TTR) é uma proteína plasmática constituída por quatro subunidades idênticas de aproximadamente 14KDa e de massa molecular de 55 KDa (Blake et al., 1978). A TTR é responsável pelo transporte de tiroxina (T4) (Andrea et al., 1980) e retinol (vitamina A), neste último tipo de transporte através da ligação à proteina de ligação ao retinol (RBP) (Kanai et al., 1968). É sintetizada principalmente pelo fígado e secretada para o sangue (Murakami et al., 1987) e também sintetizada pelas células epiteliais do plexo coróide e secretada para o líquido cefaloraquidiano (LCR) (Aleshire et al., 1983). Existem outros locais que expressam TTR mas em menor quantidade, nomeadamente: a retina do olho (Martone et al., 1988), o pâncreas (Kato et al., 1985), o saco vitelino visceral (Soprano et al., 1986) o intestino (Loughna et al., 1995); o estômago, coração, músculo e baço (Soprano et al., 1985). A TTR é uma proteína, do ponto de vista filogenético, extremamente conservada o que já de si é um indicador da sua importância biológica (Richardson, 2009) O objectivo deste trabalho foi avaliar a expressão de transtirretina ao longo do sistema gastrointestinal do murganho, nos seguintes órgãos esófago, estômago, duodeno, cólon e também bexiga, com cerca de 3 meses de idade. O segundo objectivo foi identificar as células responsáveis por essa expressão, nos órgãos em estudo. Foi possível verificar que apenas o estômago apresenta valores de expressão normalizada de TTR diferente de zero, expressão essa muito inferior à do fígado, tal como se esperava. Por imunohistoquímica/imunofluorescência foi possível determinar que as células que expressam TTR são pouco abundantes e estão presentes na região glandular do estômago do murganho e também do humano. Para além disto, verificou-se que a TTR co-localiza com somatostatina e que as células que sintetizam TTR correspondem às células D, responsáveis pela secreção de somatostatina

The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure

OBJECTIVE: Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome. PATIENTS AND METHODS: The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68+ and CD163+ macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression. RESULTS: Patients in whom BCG failed had high stroma-predominant CD163+ macrophage counts (high stroma but low tumor CD163+ macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163+ macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163+ in the tumor presented high expression of HIF-1α in tumor nests. CONCLUSIONS: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163+ macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.