2026 Poster Presentations
P199: EXPANDING GENOMIC LANDSCAPES OF PITUITARY ADENOMAS: A CASE WITH SOMATIC IDH1 MUTATION
Shashank Rajkumar, MD; Brianna C Theriault, MD, PhD; Silvio E Inzucchi, MD; Ryan A Rimmer, MD; S B Omay, MD; E Z Erson-Omay, PhD; Yale New Haven Hospital
Introduction: Pituitary adenomas are generally benign neoplasms of the anterior pituitary, classified by hormonal activity and histopathological features. Recurrent somatic mutations in GNAS, USP8, and MEN1 have been implicated in pituitary tumorigenesis, but alterations in metabolic enzymes are exceptionally rare. Isocitrate dehydrogenase 1 (IDH1) mutations, common in gliomas and other malignancies, have not been reported in pituitary adenomas. We describe a rare case of a pituitary adenoma harboring a somatic IDH1 mutation, highlighting its potential biological and clinical relevance.
Methods: We evaluated the clinical, pathological and genomics characteristics of the patient. Whole-exome sequencing (WES) was performed on the tumor and matched peripheral blood using the IDT xGen Exome Research Panel v2 with custom spike-ins targeting frequently altered cancer regions. Sequencing was conducted at the Yale Center for Genome Analysis (YCGA) on Illumina NovaSeq 600 platforms, generating paired-end 2 × 101 bp reads. Mean target coverage was 421× for the tumor and 132× for blood. Downstream analyses identified somatic single-nucleotide variants (SNVs), insertion–deletions (INDELs), and copy number variations (CNVs).
Results: The patient, an otherwise-healthy 39-year-old male, presented with headache, fatigue, and low libido, and was found to have a large sellar and suprasellar mass. He underwent endoscopic endonasal resection with an uncomplicated postoperative course and resolution of presenting symptoms. Histopathology confirmed pituitary adenoma with synaptophysin positivity, focal expression of growth hormone, Pit-1, prolactin, and ACTH, and negative staining for TSH, LH, FSH, and SF-1. Ki-67 was 3%.
WES revealed a tumor mutation burden of 0.3 mut/Mb, within the expected range for pituitary adenomas. Two somatic alterations in cancer-associated genes were identified: a hotspot IDH1 mutation (p.R132C), frequently observed in glioma, acute myeloid leukemia, and other cancers, and a splice acceptor mutation in MALT1. The IDH1 mutation had a variant allele frequency of 40%, consistent with a clonal event, whereas the MALT1 variant was subclonal (9%). No somatic CNVs or pathogenic germline variants associated with pituitary adenomas, other tumors, or cancer predisposition syndromes were detected.
Conclusion: IDH1 is a key metabolic enzyme in the tricarboxylic acid cycle, catalyzing the conversion of isocitrate to α-ketoglutarate and contributing to NADPH production. While essential for normal metabolism, mutations in IDH1—most often at codon 132—are recurrent in several cancers, where they generate the oncometabolite 2-hydroxyglutarate and drive tumorigenesis through epigenetic reprogramming. The identification of a somatic IDH1 (p.R132C) mutation in this pituitary adenoma is therefore striking and suggests a potential pathogenic role, supported by its clonal allele frequency. IDH1 mutations serve as early drivers in frequently altered tumor types (gliomas, etc.) with therapeutic implications, and targeted inhibitors are already in clinical use. Our finding expands the mutational spectrum of pituitary adenomas and underscores the value of genomic profiling to uncover clinically relevant alterations even in rare cases.