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      A Pilot Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype

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          Abstract

          Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, P = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel KCNAB2 (FDR = 5.11×10 −10). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of KCNAB2 and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.

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          Most cited references44

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          CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.

          Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors.
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            The prevalence of pituitary adenomas: a systematic review.

            Pituitary adenomas display an array of hormonal and proliferative activity. Once primarily classified according to size (microadenomas, or = 1 cm), these tumors are now further classified according to immunohistochemistry and functional status. With these additional classifications in mind, the goals of the current study were to determine the prevalence of pituitary adenomas and to explore the clinical relevance of the findings. The authors conducted a metaanalysis of all existing English-language articles in MEDLINE. They used the search string (pituitary adenoma or pituitary tumor) and prevalence and selected relevant autopsy and imaging evaluation studies for inclusion. The authors found an overall estimated prevalence of pituitary adenomas of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies). Given the high frequency of pituitary adenomas and their potential for causing clinical pathologies, the findings of the current study suggest that early diagnosis and treatment of pituitary adenomas should have far-reaching benefits.
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              DNA hypermethylation in tumorigenesis: epigenetics joins genetics.

              Recently, the concept that epigenetic, as well as genetic, events might be central to the evolution of human cancer is re-emerging. Cancers often exhibit an aberrant methylation of gene promoter regions that is associated with loss of gene function. This DNA change constitutes a heritable state, not mediated by altered nucleotide sequence, that appears to be tightly linked to the formation of transcriptionally repressive chromatin. This epigenetic process acts as an alternative to mutations to disrupt tumor-suppressor gene function and can predispose to genetic alterations through inactivating DNA-repair genes. Dissecting the molecular processes that mediate these methylation changes will enhance our understanding of chromatin modeling and gene regulation and might present novel possibilities for cancer therapy. Methylation changes constitute potentially sensitive molecular markers to define risk states, monitor prevention strategies, achieve early diagnosis, and track the prognosis of cancer.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                29 April 2014
                : 9
                : 4
                : e96178
                Affiliations
                [1 ]Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
                [2 ]Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [3 ]Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [4 ]USC Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [5 ]Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [6 ]Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [7 ]Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [8 ]Division of Bioinformatics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                [9 ]NCCC Bioinformatics Core and Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
                CEA - Institut de Genomique, France
                Author notes

                Competing Interests: Daniel J. Weisenberger is a consultant for Zymo Research, which distributes commercially available products for DNA methylation-based experiments. This work was not sponsored by Zymo Research, nor does Zymo Research have an interest in the results of this research. Mark S. Shiroishi is a consultant for Bayer Pharma AG. This work is not sponsored by Bayer nor does Bayer have an interest in the results of this research, which does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials. The authors confirm that co-author Kai Wang is an editor of PLOS ONE journal. However, this does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

                Conceived and designed the experiments: KW GZ. Performed the experiments: CL MP LS DC MSS. Analyzed the data: CL VP DJW. Contributed reagents/materials/analysis tools: CL DC MSS. Wrote the paper: CL KW GZ DJW.

                Article
                PONE-D-13-46388
                10.1371/journal.pone.0096178
                4004564
                24781529
                132cf7cc-e285-4aba-adb2-d7d430134939
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 November 2013
                : 4 April 2014
                Page count
                Pages: 13
                Funding
                The current research was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institute of Health (NIH), through Grant Award Number KL2RR031991. The content is solely the responsibility of the authors and does not necessarily represent the official view of NIH. Author Gabriel Zada is a KL2 trainee through Southern California Clinical and Translational Science Institute at University of Southern California, Keck School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Endocrine System
                Pituitary Gland
                Genetics
                Cancer Genetics
                Epigenetics
                Genetics of Disease
                Human Genetics
                Molecular Genetics
                Physiology
                Endocrine Physiology
                Population Biology
                Medicine and Health Sciences
                Endocrinology
                Epidemiology
                Cancer Epidemiology
                Genetic Epidemiology
                Oncology
                Cancers and Neoplasms
                Endocrine Tumors
                Pituitary Adenomas

                Uncategorized
                Uncategorized

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