Loss of <i>MEN1</i> activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Yuan, Ziqiang; Claros, Carmen Sánchez; Suzuki, Masako; Maggi, Elaine C.; Kaner, Justin D.; Kinstlinger, Noah; Gorecka, Jolanta; Quinn, Thomas J.; Geha, Rula C.; Corn, Amanda; Pastoriza, Jessica M.; Qiang, Jun; Adem, Asha; Wu, Hao; Alemu, Girum; Du, Yi; Zheng, Deyou; Greally, John M.; Libutti, Steven K.

doi:10.18632/oncotarget.7279

Cited by 26 publications

(14 citation statements)

References 55 publications

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“…DNA hypermethylation has been shown to occur in a subset of inherited MEN1 tumors, sporadic PNETs, sporadic pituitary tumors or sporadic parathyroid tumors at the promoter region of different genes ( APC, CTNNB1, CDKN2A /p16, CDKN2B /p15, HIC1, MEG3, MLH1, RASSF1A , and RIZ1 ), with some also correlating with respective reduction of gene expression (Carling et al 2003, Juhlin et al 2010, Lindberg et al 2008, Modali et al 2015, Svedlund et al 2012, Zhao et al 2005). A genome-wide analysis of quantitative DNA methylation in parathyroid tissue samples showed global DNA hypermethylation in menin-null parathyroid tumors from MEN1 patients, and increased transcript levels of DNMT1, predicting increased DNMT1 activity in menin-null parathyroid cells accounting for the hypermethylated DNA (Yuan et al 2016). Another study showed altered DNA methylation profiles in normal and pathologic parathyroid tissue with gene expression changes, and restored expression of hypermethylated genes upon treatment of primary cell cultures of parathyroid tumors with the DNA methylation inhibitor DAC (Starker et al 2011).…”

Section: Dna Methylation and Demethylationmentioning

confidence: 99%

Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types

Iyer

Agarwal

2018

Journal of Molecular Endocrinology

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Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non-coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor-associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss.

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Section: Dna Methylation and Demethylationmentioning

confidence: 99%

Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types

Iyer

Agarwal

2018

Journal of Molecular Endocrinology

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“…Functionally, MEN1 mutations are known to increase DNMT1 activity, which leads to global increases in CpG island methylation, a characteristic of other tumors ( Funayama et al 2013 ; Mack et al 2014 ; Yuan et al 2016 ), and silences key tumor suppressor genes, including CDKN1B, CDKN2A, APC , and RASSF1A ( Karnik et al 2005 ; Lindberg et al 2008 ; Juhlin et al 2010 ). Coupled with the observed mutations in other epigenetic regulators, these data add new evidence for epigenetic dysregulation in the genesis and progression of ependymoma.…”

Section: Discussionmentioning

confidence: 99%

Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient

Miller

Dahiya

et al. 2018

Cold Spring Harb Mol Case Stud

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As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.

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“…DNA methylation data for parathyroid tumors (accession no. GSE64412) [ 15 ] were accessed from the Gene Expression Omnibus database (GEO, http://www.ncbi.nlm.nih.gov/gds ), in the National Center for Biotechnology Information. The microarray data used the GPL11154 platform (Illumina HiSeq 2000 Homo sapiens ; Illumina Inc., San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Genomic Analysis of Abnormal DNAM Methylation in Parathyroid Tumors

Sun

et al. 2022

International Journal of Endocrinology

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Background. Parathyroid tumors are common endocrine neoplasias associated with primary hyperparathyroidism. Although numerous studies have studied the subject, the predictive value of gene biomarkers nevertheless remains low. Methods. In this study, we performed genomic analysis of abnormal DNA methylation in parathyroid tumors. After data preprocessing, differentially methylated genes were extracted from patients with parathyroid tumors by using t-tests. Results. After refinement of the basic differential methylation, 28241 unique CpGs (634 genes) were identified to be methylated. The methylated genes were primarily involved in 7 GO terms, and the top 3 terms were associated with cyst morphogenesis, ion transport, and GTPase signal. Following pathway enrichment analyses, a total of 10 significant pathways were enriched; notably, the top 3 pathways were cholinergic synapses, glutamatergic synapses, and oxytocin signaling pathways. Based on PPIN and ego-net analysis, 67 ego genes were found which could completely separate the diseased group from the normal group. The 10 most prominent genes included POLA1, FAM155 B, AMMECR1, THOC2, CCND1, CLDN11, IDS, TST, RBPJ, and GNA11. SVM analysis confirmed that this grouping approach was precise. Conclusions. This research provides useful data to further explore novel genes and pathways as therapeutic targets for parathyroid tumors.

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Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Cited by 26 publications

References 55 publications

Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types

Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types

Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient

Genomic Analysis of Abnormal DNAM Methylation in Parathyroid Tumors

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