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- Title
Genomic Alterations and Complex Subclonal Architecture in Sporadic GH-Secreting Pituitary Adenomas.
- Authors
Hage, Mirella; Viengchareun, Say; Brunet, Erika; Villa, Chiara; Pineau, Dominique; Bouligand, Jérôme; Teglas, Jean Paul; Adam, Clovis; Parker, Fabrice; Lombès, Marc; Tachdjian, Gérard; Gaillard, Stéphane; Chanson, Philippe; Tosca, Lucie; Kamenický, Peter
- Abstract
<bold>Purpose: </bold>The molecular pathogenesis of growth hormone-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation-negative somatotroph tumors.<bold>Experimental Design: </bold>We performed cytogenetic profiling of pituitary adenomas obtained from 39 patients with acromegaly and four patients with sporadic gigantism by using array comparative genomic hybridization analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH).<bold>Results: </bold>Based on copy-number profiles, we found two groups of adenomas: a low-copy-number alteration (CNA) group (<12% of genomic disruption, 63% of tumors) and a high-CNA group (24% to 45% of genomic disruption, 37% of tumors). Arm-level CNAs were the most common abnormalities. GNAS mutation-positive adenomas belonged exclusively to the low-CNA group, whereas a subgroup of GNAS mutation-negative adenomas had a high degree of genomic disruption. We detected chromothripsis-related CNA profiles in two adenoma samples from an AIP mutation-positive patient with acromegaly and a patient with sporadic gigantism. RNA sequencing of these two samples identified 17 fusion transcripts, most of which resulted from chromothripsis-related chromosomal rearrangements. DNA FISH analysis of these samples demonstrated a subclonal architecture with up to six distinct cell populations in each tumor.<bold>Conclusion: </bold>Somatotroph pituitary adenomas display substantial intertumor and intratumor DNA copy-number heterogeneity, as revealed by variable CNA profiles and complex subclonal architecture. The extensive cytogenetic burden in a subgroup of GNAS mutation-negative somatotroph adenomas points to an alternative tumorigenic pathway linked to genomic instability.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2018, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2017-02287