Journal Article

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

Adam, Clovis, Tosca, Lucie, Lombès, Marc, Gaillard, Stéphane, Brunet, Erika, Parker, Fabrice, Villa, Chiara, Pineau, Dominique, Tachdjian, Gérard, Teglas, Jean-Paul, Hage, Mirella, Viengchareun, Say, Chanson, Philippe, Bouligand, Jérôme, Kamenický, Peter

2018

Overview

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. Using cytogenetic profiling and DNA FISH analysis, we identified extensive intertumor and intratumor DNA copy-number heterogeneity reflecting a complex clonal architecture in somatotroph adenomas.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Acromegaly / Acromegaly - genetics / Acromegaly - pathology / Adenoma / Adenoma - genetics / Adenoma - pathology / Adult / Chromosome Aberrations / Chromosome rearrangements / Clonal Evolution - genetics / Comparative Genomic Hybridization / Cytogenetic Analysis / Cytogenetics / Deoxyribonucleic acid / DNA / DNA Copy Number Variations / DNA fingerprinting / Endocrinology and metabolism / Female / Fluorescence in situ hybridization / Genomic analysis / Genomic instability / Gigantism / Growth Hormone-Secreting Pituitary Adenoma - genetics / Growth Hormone-Secreting Pituitary Adenoma - pathology / Growth hormones / Human health and pathology / Humans / Hybridization analysis / In Situ Hybridization, Fluorescence / Life Sciences / Male / Middle Aged / Mutation / Pituitary / Ribonucleic acid / RNA / Tumors