Longitudinal multiomics analysis of aggressive pituitary neuroendocrine tumors: comparing primary and recurrent tumors from the same patient, reveals genomic stability and heterogeneous transcriptomic profiles with alterations in metabolic pathways.

Abstract

Pituitary neuroendocrine tumors (PitNET) represent the vast majority of sellar masses. Some behave aggressively, growing rapidly and invading surrounding tissues, with high rates of recurrence and resistance to therapy. Our aim was to establish patterns of genomic, transcriptomic and methylomic evolution throughout time in primary and recurrent tumors from the same patient. Therefore, we performed transcriptome- and exome-sequencing and methylome microarrays of aggressive, primary, and recurrent PitNET from the same patient. Primary and recurrent tumors showed a similar exome profile, potentially indicating a stable genome over time. In contrast, the transcriptome of primary and recurrent PitNET was dissimilar. Gonadotroph, silent corticotroph, as well as metastatic corticotroph and a somatotroph PitNET expressed genes related to fatty acid biosynthesis and metabolism, phosphatidylinositol signaling, glycerophospholipid and phospholipase D signaling, respectively. Diacylglycerol kinase gamma (DGKG), a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways, was differentially expressed between primary and recurrent PitNET. These alterations did not seem to be regulated by DNA methylation, but rather by several transcription factors. Molecular docking showed that dasatinib, a small molecule tyrosine kinase inhibitor used in the treatment of chronic lymphocytic and acute lymphoblastic leukemia, could target DGKG. Dasatinib induced apoptosis and decreased proliferation in GH3 cells. Our data indicate that pituitary tumorigenesis could be driven by transcriptomically heterogeneous clones, and we describe alternative pharmacological therapies for aggressive and recurrent PitNET.