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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Cushing disease, caused by hormone excess from pituitary tumors, presents variable clinical behaviors.
  • Tumor aggressiveness and hormone secretion levels differ among patients, suggesting underlying genetic factors.
  • Fibroblast growth factor receptor 4 (FGFR4) is implicated in cellular processes relevant to tumor development.

Purpose of the Study:

  • To investigate the role of FGFR4 transmembrane domain polymorphisms in Cushing disease pathogenesis.
  • To determine how different FGFR4 variants affect pituitary tumor cell growth and hormone feedback mechanisms.
  • To correlate FGFR4 genotypes with clinical presentation and tumor characteristics in patients.

Main Methods:

  • Analysis of FGFR4 transmembrane domain polymorphisms and their functional effects on receptor signaling.
  • Assessment of signal transducer and activator of transcription (STAT3) phosphorylation and glucocorticoid receptor activity.
  • Evaluation of hormone negative feedback in mouse models with specific FGFR4 alleles.
  • Correlation of FGFR4 genotypes with pituitary tumor types and clinical data from patients.

Main Results:

  • The FGFR4-G388 variant supports STAT3 phosphorylation on tyrosine, while the FGFR4-R388 variant enhances STAT3 serine phosphorylation, promoting cellular growth.
  • FGFR4-R388 also increases glucocorticoid receptor phosphorylation and nuclear translocation, potentially affecting hormone feedback.
  • Mice with the FGFR4 variant allele showed enhanced glucocorticoid negative feedback.
  • Patients homozygous for FGFR4-R388 had a higher incidence of silent corticotroph macroadenomas, whereas G388 carriers were more prone to hormonally active microadenomas.

Conclusions:

  • FGFR4 transmembrane polymorphic variants significantly influence cellular growth and glucocorticoid hormone feedback sensitivity.
  • Distinct STAT3 modifications mediated by FGFR4 variants are relevant to the pathogenesis of human Cushing disease.
  • FGFR4 genotype may serve as a biomarker for predicting pituitary tumor behavior and clinical outcomes in Cushing disease.