Transcriptome analysis showed a Differential signature between invasive and non-invasive corticotrophinomas

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP ARAUJO, Leonardo Jose Tadeu de FMUSP-HC
LERARIO, Antonio Marcondes FMUSP-HC
CASTRO, Margaret de
MARTINS, Clarissa Silva
FRAGOSO, Maria Candida Barisson Villares FMUSP-HC 2017
dc.identifier.citation FRONTIERS IN ENDOCRINOLOGY, v.8, article ID 55, 12p, 2017
dc.identifier.issn 1664-2392
dc.description.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 (approximate to 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 in USP8 were also investigated, but none of the patients exhibited USP8 variants. 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 highlighted CCND2, ZNF676, DAPK1, and TIMP2, 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-beta 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.
dc.description.sponsorship · Sao Paulo Research Foundation (FAPESP) [2012/17395-5]
· Technological and Scientific Development National Council (CnPQ) [307022/20129]
dc.language.iso eng
dc.relation.ispartof Frontiers in Endocrinology
dc.rights openAccess
dc.subject Cushing's disease; gene expression; neuroendocrine tumors; microarray; anterior pituitary
dc.subject.other growth-factor receptor-4; tumor-transforming gene; secreting pituitary-adenomas; cell-cycle regulators; cushings-disease; promoter hypermethylation; protein-kinase; pttg expression; size; amplification
dc.title Transcriptome analysis showed a Differential signature between invasive and non-invasive corticotrophinomas
dc.type article
dc.rights.holder Copyright FRONTIERS MEDIA SA LIM/25 LIM/42
dc.identifier.doi 10.3389/fendo.2017.00055
dc.identifier.pmid 28382019
dc.type.category original article
dc.type.version publishedVersion ARAUJO, Leonardo Jose Tadeu de:FM: LERARIO, Antonio Marcondes:HC:ICESP BRONSTEIN, Marcello Delano:HC:ICHC MACHADO, Marcio Carlos:HC:ICHC TRARBACH, Ericka Barbosa:HC:LIM/25 FRAGOSO, Maria Candida Barisson Villares:HC:ICHC · CASTRO, Margaret de:Univ Sao Paulo, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil
· MARTINS, Clarissa Silva:Univ Sao Paulo, Dept Internal Med, Ribeirao Preto Med Sch, Ribeirao Preto, Brazil 2-s2.0-85017104430 WOS:000397148300001 LAUSANNE SWITZERLAND
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