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 (Gαs encoded by GNAS) 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 GNAS mutation negative (Gsp- ). The chromosome stable (CS) -group contained Gsp+ somatotropinomas and two totally aneuploidy-free Gsp- tumors. Genes related to the mitotic G1-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 Gsp genotype-specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gαi) signaling is activated in Gsp+ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp- somatotropinomas, whereas Gsp+ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gαi 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.

Välimäki N ，Schalin-Jäntti C ，Karppinen A ，Paetau A ，Kivipelto L ，Aaltonen LA ，Karhu A ... -  《-》

Somatotroph Tumors and the Epigenetic Status of the GNAS Locus.

Romanet P ，Galluso J ，Kamenicky P ，Hage M ，Theodoropoulou M ，Roche C ，Graillon T ，Etchevers HC ，De Murat D ，Mougel G ，Figarella-Branger D ，Dufour H ，Cuny T ，Assié G ，Barlier A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas.

Välimäki N ，Demir H ，Pitkänen E ，Kaasinen E ，Karppinen A ，Kivipelto L ，Schalin-Jäntti C ，Aaltonen LA ，Karhu A ... -  《-》

Clinical Identification of Oncogenic Drivers and Copy-Number Alterations in Pituitary Tumors.

Pituitary tumors are the second most common adult primary brain tumor, with a variable clinical course. Recent work has identified a number of genetic determinants of pituitary tumor subtypes, which may augment traditional histopathologic classification schemes. We sought to determine whether pituitary tumors could be stratified based on objective molecular characteristics using a clinical genomics assay. We performed a retrospective analysis of patients operated on at the Brigham and Women's Hospital from 2012 to 2016 whose pituitary tumors were profiled using multiplexed next-generation sequencing. We analyzed 127 pituitary tumors, including 114 adenomas, 5 craniopharyngiomas, and 8 tumors of other histologies. We observed recurrent BRAFV600E mutations in papillary craniopharyngiomas, CTNNB1 mutations in adamantinomatous craniopharyngiomas, and activating GNAS mutations in growth hormone-secreting adenomas. Furthermore, we validated the presence of two distinct genomic subclasses in adenomas (i.e., those with disrupted or quiet copy-number profiles) and the significant association of disruption with functional hormone status (P < 0.05). We report the clinical implementation of next-generation sequencing of pituitary tumors. We confirmed previously identified molecular subclasses for these tumors and show that routine screening as part of clinical practice is both feasible and informative. This large-scale proof-of-principle study may help to guide future institutional efforts for pituitary tumor classification as well as the incorporation of such techniques into prospective analysis as part of clinical trials.

Bi WL ，Greenwald NF ，Ramkissoon SH ，Abedalthagafi M ，Coy SM ，Ligon KL ，Mei Y ，MacConaill L ，Ducar M ，Min L ，Santagata S ，Kaiser UB ，Beroukhim R ，Laws ER Jr ，Dunn IF ... -  《-》

Elevation of growth hormone-releasing hormone receptor messenger ribonucleic acid expression in growth hormone-secreting pituitary adenoma with Gsalpha protein mutation.

Sakai N ，Kim K ，Sanno N ，Yoshida D ，Teramoto A ，Shibasaki T ... -  《-》