Papel da via lkaros-FGFR4 na evolução pós-cirúrgica dos pacientes com doença de Cushing / Ikaros-FGFR4 pathway: role in the postoperative outcome of Cushings disease

AUTOR(ES)
DATA DE PUBLICAÇÃO

2010

RESUMO

Introduction: The mechanisms involved in the molecular pathogenesis of corticotroph pituitary tumors are complex, heterogeneous and in most cases remain unknown. Changes in the expression of components of Ikaros (Ik) pathway, such as receptor 4 of fibroblast growth factor (FGFR4), have been detected in pituitary tumors including corticotropinomas. Imbalance between long and short Ik isoforms results in alternative transcription initiation of FGFR4 and encodes a truncated isoform of the gene (pdt-FGFR4) which was associated with larger and more invasive pituitary tumors. The Ik6 short isoform promotes Bcl-XL expression in vitro, an effect independent of the interaction with the long isoforms. In addition, a polymorphism of FGFR4 gene, the substitution of glycine by arginine at codon 388 (G388R), has been associated with adverse outcome in several human tumor types. Objectives: To analyze the expression of Bcl-XL, Ikaros isoforms (Ik1 + Ik2/Ikaros total), and FGFR4 in human corticotropinomas. To determine the frequency of each genotype at codon 388 of FGFR4 in patients with Cushings disease and its association with the postoperative outcome after the first transsphenoidal surgery. Methods: Ninety-seven patients with Cushings disease were evaluated. Clinical, hormonal and histopathological findings were assessed retrospectively. The expression of Bcl-XL, Ikaros and FGFR4 were evaluated by real-time PCR in 20 samples of corticotropinomas, including two samples of Nelsons syndrome. The FGFR4 genotype was determined in the 97 patients and 103 control subjects by PCR fragment of exon 9 of the FGFR4 gene, followed by digestion with the BstNI restriction enzyme. The postoperative outcome (remission/relapse) of Cushings disease was assessed in 76 patients. The patients with normal urinary cortisol levels during the first year after surgery, in the absence of hormone replacement therapy, and those who required glucocorticoid replacement within the same period were considered in remission. Results: Of the 76 patients who underwent the first transsphenoidal surgery, remission was achieved in 68.4% of patients. Thirteen patients (25%) developed recurrence of Cushings disease after initial remission. The expression of Bcl-XL in the majority of tumor samples was similar to normal pituitary [median (min-max): 1.36 (0.6 - 2.70)]. Overexpression of long isoforms of Ik was detected in 40% of tumors, while the short isoforms represented more than 50% of the expression in only 3 samples. Ik expression was not associated with any of the variables analysed. FGFR4 transcripts were overexpressed in 8/18 (44.4%) of corticotropinomas with Cushings disease. There was an association between the overexpression of FGFR4 and lower postoperative remission rate (p = 0.009). The FGFR4 genotype distribution at codon 388 was similar between control individuals and patients. The glycine homozygous genotype (Gly/Gly) was not associated with lower remission rate. However, a higher frequency of postoperative recurrence was found in the Gly/Gly group (p = 0.019). The Gly/Gly genotype was also associated with reduced disease-free survival (hazard ratio [HR] 6.91, confidence interval (CI) 95%, 1.14 to 11.26; p = 0.028). Other variables that were significantly associated with higher frequency of recurrence were: size and tumor invasion according to modified Hardy classification (p = 0.017), male gender (p = 0.033), non-immuno-histological confirmation of ACTH secreting tumor (p = 0.026) and cortisol levels >2 ?g/dL in the early postoperative period (p = 0.01). Conclusions: The normal expression of Bcl-XL and short isoforms of Ik in most samples suggest that these factors are not involved in the pathogenesis of corticotroph tumors. Overexpression of FGFR4 and the glycine homozygous genotype were associated with lower frequency of remission and higher postoperative recurrence of Cushings disease, respectively. These results suggest that FGFR4 may play a role in progression of corticotroph tumors favoring the persistence and/or recurrence of Cushings disease.

ASSUNTO(S)

acth- secreting pituitary adenoma/etiology recurrence/prevention &control polimorfismo genético/genética receptors fibroblast growth factor/genetics fatores de transcrição/fisiologia transcription factors/physiology expressão gênica/genética recidiva/prevenção &controle gene expression/genetics receptores de fator de crescimento de fibroblastos/genética adenoma hipofisário secretor de acth/etiologia polymorphism/genetics

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