DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features

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Mosella, Maritza S. ^{[1, 2]} ; Sabedot, Thais S. ^[2] ; Silva, Tiago C. ^{[1, 3]} ; Malta, Tathiane M. ^{[4, 2]} ; Dezem, Felipe Segato ^{[1, 5]} ; Asmaro, Karam P. ^[6] ; Wells, Michael ^[2] ; Mukherjee, Abir ^[7] ; Poisson, Laila M. ^{[2, 8]} ; Snyder, James ^[2] ; deCarvalho, Ana C. ^[2] ; Walbert, Tobias ^[2] ; Aho, Todd ^[9] ; Kalkanis, Steven ^[6] ; Elias, Paula C. ^[10] ; Antonini, Sonir R. ^[11] ; Rock, Jack ^[6] ; Noushmehr, Houtan ^{[1, 2]} ; Castro, Margaret ^[10] ; Castrot, Ana Valeria ^[2]

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^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP - Brazil

^[2] Henry Ford Hlth Syst, Hermelin BrainTumor Ctr, Henry Ford Canc Inst, Detroit, MI 48202 - USA

^[3] Univ Miami, Coral Gables, FL 33124 - USA

^[4] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[5] Cedars Sinai Med Ctr, Los Angeles, CA 90048 - USA

^[6] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 - USA

^[7] Henry Ford Hlth Syst, Dept Pathol, Detroit, MI 48202 - USA

^[8] Henry Ford Hlth Syst, Ctr Bioinformat, Dept Publ Hlth Sci, Detroit, MI 48202 - USA

^[9] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI 48202 - USA

^[10] Univ Sao Paulo, Ribeirao Preto Med Sch, Internal Med Dept, Ribeirao Preto, SP - Brazil

^[11] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NEURO-ONCOLOGY; v. 23, n. 8, p. 1292-1303, AUG 2021.
• Citações Web of Science: 0

Resumo

Background. Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups. Methods. Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings. Results. We identified three methylation dusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors. Conclusions. We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status.These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors. (AU)

• Processo FAPESP: 16/11039-3 - Traçando Assinaturas epigenômicas de tumores com Fenótipo de Ilhas CpG Metiladas (CIMP)
• Beneficiário: Maritza Queiroz Salas Mosella
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/03989-6 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-Generation Sequencing)
• Beneficiário: Margaret de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/10357-4 - Análise Compreensiva e Integrativa do Metiloma de Tumores Endócrinos que apresentam o Fenótipo de Hipermetilação de Ilhas CpG (CIMP)
• Beneficiário: Maritza Queiroz Salas Mosella
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado