DNA Methylation of Tumor Suppressor Genes in Pituitary Neuroendocrine Tumors

Abstract Context Epigenetic alterations may play a role in the development and behavior of pituitary neuroendocrine tumors (PitNETs). Objective To evaluate the effect of methylation of tumor suppressor genes (TSGs) on their gene expression and on the behavior of PitNETs. Material and Methods We used...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2019-04, Vol.104 (4), p.1272-1282
Main Authors: García-Martínez, Araceli, Sottile, Johana, Sánchez-Tejada, Laura, Fajardo, Carmen, Cámara, Rosa, Lamas, Cristina, Barberá, Victor Manuel, Picó, Antonio
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Analysis
Deoxyribonucleic acid
DNA
DNA Methylation
Epigenesis, Genetic
Epigenetic inheritance
ESR1 protein
Female
Gene expression
Gene Expression Regulation
Gene Expression Regulation, Neoplastic
Genes
Genes, Tumor Suppressor
Humans
Invasiveness
Magnetic resonance imaging
Methylation
Middle Aged
MSH6 protein
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
Neuroendocrine tumors
Neuroendocrine Tumors - genetics
Neuroendocrine Tumors - pathology
Pituitary
Pituitary (anterior)
Pituitary Gland - pathology
Pituitary Neoplasms - genetics
Pituitary Neoplasms - pathology
Promoter Regions, Genetic - genetics
Tumor Burden - genetics
Tumor suppressor genes
Tumors
Young Adult
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Summary:Abstract Context Epigenetic alterations may play a role in the development and behavior of pituitary neuroendocrine tumors (PitNETs). Objective To evaluate the effect of methylation of tumor suppressor genes (TSGs) on their gene expression and on the behavior of PitNETs. Material and Methods We used methylation-specific multiplex ligation-dependent probe amplification and quantitative real-time PCR techniques to analyze the DNA-promoter hypermethylation and gene expression of 35 TSGs in 105 PitNETs. We defined functionality, size, and invasiveness of tumors according to their clinical manifestations, Hardy’s classification, and MRI invasiveness of the cavernous sinus, respectively. Results We observed different methylation patterns among PitNET subtypes. The methylation status of TP73 correlated negatively with its gene expression in the overall series (P = 0.013) and in some subtypes. MSH6 and CADM1 showed higher methylation frequency in macroadenomas than in microadenomas in the overall series and in corticotroph PitNETs (all P ≤ 0.053). ESR1 and RASSF1 were more highly methylated in noninvasive than in invasive tumors in the overall series (P = 0.054 and P = 0.031, respectively) and in the gonadotroph subtype (P = 0.055 and P = 0.050, respectively). ESR1 and CASP8 appeared more hypermethylated in functioning than in silent corticotroph tumors (P = 0.034 and P = 0.034, respectively). Conclusions DNA methylation of TSGs has a selective effect on their gene expression and on the growth and invasiveness of PitNETs. Its involvement in their functionality is biased because all silent operated tumors are macroadenomas, whereas all operated microadenomas are functioning ones. Therefore, the subtypes of PitNETs should be considered different entities. The study of methylation status of 35 TSGs in a series of 105 PitNETs allowed us to show a selective effect on gene expression and on the clinical behavior and functionality of these tumors.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2018-01856