title: Transcriptome Analysis Showed a Differential Signature between Invasive and Non-invasive Corticotrophinomas.
abstract: ACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing's disease (CD)] is the most common cause of endogenous Cushing's syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (≈80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, ≥10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n= 4) and MAC (n= 5), and invasive MAC (n= 3), according to modified Hardy criteria. Somatic mutations inUSP8were also investigated, but none of the patients exhibitedUSP8variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlightedCCND2, ZNF676, DAPK1, andTIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-β and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.
authors.affiliation: Laboratory of Hormones and Molecular Genetics LIM-42, University of São Paulo Medical School, São Paulo, Brazil; Laboratory of Quantitative Pathology, Center of Pathology, Adolfo Lutz Institute, São Paulo, Brazil.
authors.forename: Leonardo Jose Tadeu
authors.initials: LJ
authors.lastname: de Araújo
authors.affiliation: Laboratory of Hormones and Molecular Genetics LIM-42, University of São Paulo Medical School, São Paulo, Brazil; Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Antonio Marcondes
authors.initials: AM
authors.lastname: Lerario
authors.affiliation: Internal Medicine Department, Ribeirao Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil.
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.affiliation: Internal Medicine Department, Ribeirao Preto Medical School, University of São Paulo , Ribeirao Preto , Brazil.
authors.forename: Clarissa Silva
authors.initials: CS
authors.lastname: Martins
authors.affiliation: Laboratory of Hormones and Molecular Genetics LIM-42, University of São Paulo Medical School, São Paulo, Brazil; Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Marcello Delano
authors.initials: MD
authors.lastname: Bronstein
authors.affiliation: Laboratory of Hormones and Molecular Genetics LIM-42, University of São Paulo Medical School, São Paulo, Brazil; Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School, São Paulo, Brazil; Endocrinology Service, AC Cancer Center, São Paulo, Brazil.
authors.forename: Marcio Carlos
authors.initials: MC
authors.lastname: Machado
authors.affiliation: Laboratory of Cellular and Molecular Endocrinology LIM-25, University of São Paulo Medical School , São Paulo , Brazil.
authors.forename: Ericka Barbosa
authors.initials: EB
authors.lastname: Trarbach
authors.affiliation: Laboratory of Hormones and Molecular Genetics LIM-42, University of São Paulo Medical School, São Paulo, Brazil; Endocrinology Service, AC Cancer Center, São Paulo, Brazil.
authors.forename: Maria Candida Barisson
authors.initials: MC
authors.lastname: Villares Fragoso
keywords: Cushing’s disease; anterior pituitary; gene expression; microarray; neuroendocrine tumors