Genetic and Epigenetic Characterization of Growth Hormone-Secreting Pituitary Tumors.

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Gα protein (Gα encoded by ) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were mutation negative ( ). The chromosome stable (CS) -group contained somatotropinomas and two totally aneuploidy-free tumors. Genes related to the mitotic G-S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct genotype-specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gα) signaling is activated in tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in somatotropinomas, whereas tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gα signaling. IMPLICATIONS: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.