Expression of pituitary tumour-derived, N-terminally truncated isoform of fibroblast growth factor receptor 4 (ptd-FGFR4) correlates with tumour invasiveness but not with G-protein alpha subunit (gsp) mutation in human GH-secreting pituitary adenomas.
OBJECTIVE
Apart from the constitutively activating mutation of the G-protein alpha subunit (Gsalpha) (gsp mutation), factors involved in tumorigenesis or those in tumour behaviour remain elusive in sporadic GH-secreting pituitary adenomas. Recently, the N-terminally truncated form of fibroblast growth factor receptor-4 (ptd-FGFR4) was identified in pituitary adenomas. This aberrant receptor has transforming activity, and causes pituitary adenomas in transgenic mice. The clinical relevance of this receptor warrants investigation. Our objective was twofold: first, to examine how the expression of ptd-FGFR4 relates to gsp mutations; and second, to see whether patients with this receptor have unique clinical characteristics.


METHODS
mRNA was extracted from excised adenomas of 45 Japanese acromegalic patients. ptd-FGFR4 expression and gsp mutations were determined by reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing. Preoperative clinical data were collected by reviewing medical charts and pituitary magnetic resonance imaging (MRI) scans.


RESULTS
ptd-FGFR4 mRNA expression was detected in 19 out of 45 tumours (42.2%) while gsp mutations were detected in 25 out of 45 tumours (55.6%). The prevalence of ptd-FGFR4 expression did not differ between gsp-positive (44.0%) and gsp-negative (40.0%) tumours (P = 1.00). ptd-FGFR4-positive tumours invaded the cavernous sinus more frequently (P = 0.0098) than did the ptd-FGFR4-negative tumours. Tumour size was not statistically different between ptd-FGFR4-positive and -negative tumours (P = 0.198). The presence of ptd-FGFR4 did not correlate with age at operation, sex, preoperative serum GH or IGF-1 levels.


CONCLUSIONS
We found that ptd-FGFR4 expression and gsp mutations occur independently of each other, and that ptd-FGFR4 expression is associated with more invasive tumours in patients with GH-secreting pituitary adenomas.
Morita
Koji
K
Department of Nephrology and Endocrinology, University of Tokyo Faculty of Medicine, Tokyo, Japan. ktakano-tky@uminutesac.jp
Takano
Koji
K
Yasufuku-Takano
Junko
J
Yamada
Shozo
S
Teramoto
Akira
A
Takei
Mao
M
Osamura
Robert Yoshiyuki
RY
Sano
Toshiaki
T
Fujita
Toshiro
T
D000328:Adult; D020816:Amino Acid Motifs; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D044385:GTP-Binding Protein alpha Subunits; D020033:Protein Isoforms; D051499:Receptor, Fibroblast Growth Factor, Type 4