Genomic Alterations and Complex Subclonal Architecture in Sporadic GH-Secreting Pituitary Adenomas.

Abstract

Purpose:

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.

Experimental Design:

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).

Results:

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.

Conclusion:

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.

• Authors: Mirella Hage, Say Viengchareun, Erika Brunet, Chiara Villa, Dominique Pineau, Jérôme Bouligand, Jean-Paul Teglas, Clovis Adam, Fabrice Parker, Marc Lombès, Gérard Tachdjian, Stéphane Gaillard, Philippe Chanson, Lucie Tosca, Peter Kamenický
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 5 Pg. 1929-1939 (05 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 29474559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Acromegaly (genetics, pathology)
• Adenoma (genetics, pathology)
• Adult
• Chromosome Aberrations
• Clonal Evolution (genetics)
• Comparative Genomic Hybridization
• Cytogenetic Analysis
• DNA Copy Number Variations
• Female
• Growth Hormone-Secreting Pituitary Adenoma (genetics, pathology)
• Humans
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Mutation