A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas.
OBJECTIVE
Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas.


METHODS
We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses.


RESULTS
In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses.


CONCLUSIONS
IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. olivera.casar-borota@igp.uu.se.|Department of Clinical Pathology and Cytology, Uppsala University Hospital, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden. olivera.casar-borota@igp.uu.se.|Department of Pathology, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway. olivera.casar-borota@igp.uu.se.
Olivera
O
Casar-Borota
Department of Specialised Endocrinology, Oslo University Hospital, Sognsvannsveien 20, 0372, Oslo, Norway.|Faculty of Medicine, University of Oslo, Klaus Torgårdsvei 3, 0372, Oslo, Norway.
Kristin Astrid Berland
KA
Øystese
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.|Department of Clinical Pathology and Cytology, Uppsala University Hospital, Rudbeck Laboratory, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
Magnus
M
Sundström
Department of Pathology, Rigshospitalet Copenhagen University Hospital, Frederik V's vei 11, 2100, Copenhagen, Denmark.
Linea
L
Melchior
Medical Faculty, University of Belgrade, Dr Subotica 8, 11 000, Belgrade, Serbia.
Vera
V
Popovic
D049913:ACTH-Secreting Pituitary Adenoma / Q000378:metabolism; D000236:Adenoma / Q000378:metabolism*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D009347:Nelson Syndrome / Q000378:metabolism; D047748:Pituitary ACTH Hypersecretion / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000378:metabolism*; D015175:Prolactinoma / Q000378:metabolism; D012189:Retrospective Studies; D046888:Tissue Array Analysis
D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
IDH1(R132H); Immunohistochemistry; Isocitrate dehydrogenase; Pituitary adenoma; Tissue microarrays