Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Abstract

Context: Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. Aim: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. Design: Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (nZ31) and next-generation exome sequencing (nZ36). Results: By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed. Conclusion: This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.

The genetic background of acromegaly

“…No novel recurrent mutated genes were identified. In agreement with these findings, Ronchi et al performed a next-generation whole-exome sequencing in 36 sporadic somatotropinomas, identifying a median of three mutations per sample [86]. Again, the only recurrent somatic mutation observed was in the GNAS gene (31.4% of the cases).…”

“…To identify further somatic mutations in sporadic somatotroph adenomas exome [83, 86] and whole genome sequencing studies were performed [87]. Välimäki et al performed a whole-genome sequencing and single-nucleotide polymorphism (SNP) array in 12 fresh-frozen somatotropinomas and in the leucocyte DNA of the corresponding patients [87].…”

“…In the study by Ronchi et al, seven genes involved in the cAMP signaling pathway were affected in 14 of the 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism [86]. In the study by Välimäki et al, five genes involved in cAMP or calcium-related signaling pathways were found to be mutated [87].…”

MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma

“…BRAF and KRAS mutations are uncommon in pituitary adenomas (Newey et al, 2013;Reincke et al, 2015;Ronchi et al, 2016;Välimäki et al, 2015), but the overactivation of the MAPK/ERK pathway has been reported in these neoplasias. A mutation was identified in codon 12 of the HRAS gene (Gly to Val) in a recurrent prolactinoma that was highly invasive and ultimately proved to be fatal (Karga et al, 1992).…”

Landscape of Genomic Alterations in Pituitary Adenomas

“…These include AIP , MEN1 , CDKN1B , and PRKAR1A (5–8). Recently, somatic mutations in the deubiquitinase gene USP8 and a G-protein-coupled receptor GPR101 on a microduplicated region of Xq26.3 have been identified in Cushing’s disease and young-onset acromegaly, respectively, along with GNAS mutations in a subset of GH tumors (9–11). For the majority of pituitary tumors, however, genetic events that contribute to tumorigenesis remain unknown.…”