Role of Nucleosomal Occupancy in the Epigenetic Silencing of the MLH1 CpG Island

The adenomatous polyposis coli (APC) gene, known as tumor suppressor gene, has the two promoters 1A and 1B. Researches on APC have usually focused on its loss-of-function variants causing familial adenomatous polyposis. Hypermethylation, however, which is one of the key epigenetic alterations of the APC CpG sequence, is also associated with carcinogenesis in various cancers. Accumulating studies have successively explored the role of APC hypermethylation in gastrointestinal (GI) tumors, such as in esophageal, colorectal, gastric, pancreatic, and hepatic cancer. In sporadic colorectal cancer, the hypermethylation of CpG island in APC is even considered as one of the primary causative factors. In this review, we systematically summarized the distribution of APC gene methylation in various GI tumors, and attempted to provide an improved general understanding of DNA methylation in GI tumors. In addition, we included a robust overview of demethylating agents available for both basic and clinical researches. Finally, we elaborated our findings and perspectives on the overall situation of APC gene methylation in GI tumors, aiming to explore the potential research directions and clinical values.

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The Role of Methylation in the CpG Island of the ARHI Promoter Region in Cancers

Advances in Experimental Medicine and Biology - Single-cell Sequencing and Methylation ◽

10.1007/978-981-15-4494-1_10 ◽

2020 ◽

pp. 123-132

Author(s):

Xiaozhuan Liu ◽

Tingting Zhang ◽

Yanjun Li ◽

Yuwei Zhang ◽

Hui Zhang ◽

...

Keyword(s):

Promoter Region ◽

Cpg Island

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Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708914114 ◽

2017 ◽

Vol 114 (40) ◽

pp. 10743-10748 ◽

Cited By ~ 54

Author(s):

Tali Mazor ◽

Charles Chesnelong ◽

Aleksandr Pankov ◽

Llewellyn E. Jalbert ◽

Chibo Hong ◽

...

Keyword(s):

Copy Number ◽

Cpg Island ◽

Clonal Expansion ◽

Low Grade ◽

Copy Number Alterations ◽

Wild Type ◽

Mutant Idh1

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

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Tu1669 Role of MicroRNA-31 Expression and CpG Island Methylator Phenotype in the Progression of Serrated Lesion

Gastroenterology ◽

10.1016/s0016-5085(14)62945-0 ◽

2014 ◽

Vol 146 (5) ◽

pp. S-814

Author(s):

Katsuhiko Nosho ◽

Hisayoshi Igarashi ◽

Shinji Yoshii ◽

Miki Ito ◽

Takafumi Naito ◽

...

Keyword(s):

Cpg Island ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Serrated Lesion

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The Role of piRNA-Mediated Epigenetic Silencing in the Population Dynamics of Transposable Elements in Drosophila melanogaster

PLoS Genetics ◽

10.1371/journal.pgen.1005269 ◽

2015 ◽

Vol 11 (6) ◽

pp. e1005269 ◽

Cited By ~ 62

Author(s):

Yuh Chwen G. Lee

Keyword(s):

Population Dynamics ◽

Drosophila Melanogaster ◽

Transposable Elements ◽

Epigenetic Silencing

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The Role of DNA Methylation of HoxA5, a Regulator of Haematopoiesis, in Progression to Myeloid Blast Crisis in CML.

Blood ◽

10.1182/blood.v104.11.2053.2053 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2053-2053

Author(s):

Gordon R. Strathdee ◽

Tessa L. Holyoake ◽

Alyson Sim ◽

Robert Brown

Keyword(s):

Dna Methylation ◽

Cpg Island ◽

Blast Crisis ◽

Chronic Phase ◽

Prognostic Indicator ◽

Myeloid Differentiation ◽

Direct Role ◽

Risk Of Progression ◽

Sokal Score

Abstract Hox (homeobox) genes are known to be key regulators of development and haematopoiesis and several have also been implicated in leukaemogenesis. Overexpression of HoxA5 in human haematopoietic progenitors leads to an increase in myelopoiesis, suggesting a role for this hox gene during induction of myeloid differentiation. Inactivation of genes by CpG island DNA methylation is known to be important in the development and progression of leukaemia, and inhibitors of DNA methylation are currently of great interest as novel therapeutics for a number of haematopoietic malignancies. Here we show that in peripheral blood from healthy volunteers HoxA5 exhibits methylation of 50% of alleles across an extensive CpG island covering the promoter region/1st exon of HoxA5. In patients with chronic myeloid leukaemia, 33% (15/45 patients) exhibited increased methylation of HoxA5 (80–100% of alleles methylated) in the chronic phase of the disease. However, such hypermethylation of HoxA5 was invariably present in samples from patients in myeloid blast crisis (15/15 patients). In contrast, patients in lymphoid blast crisis did not exhibit increased levels of hypermethylation. Analysis of patients in chronic phase demonstrated a statistically significant correlation (p < 0.006) between hypermethylation of the HoxA5 gene and other prognostic factors associated with high risk of progression to blast crisis (high Hasford/Sokal score, incomplete response to Imatinib, known early progression, del 9), suggesting that methylation of HoxA5 may be a clinically useful prognostic indicator. The results are also compatible with a direct role for hypermethylation of HoxA5, and consequent loss of HoxA5 expression, in inhibition of myeloid differentiation during progression to blast crisis and implicate HoxA5 as a therapeutic target for inhibitors of DNA methylation in the treatment of leukaemia.

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BIK (Bcl2-Interacting Killer) CpG Methylation Status in Multiple Myeloma Patients: a Potential Predictor of Relapsed/Refractory Disease.

Blood ◽

10.1182/blood.v114.22.2397.2397 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2397-2397

Author(s):

Eleftheria Hatzimichael ◽

Aggeliki Dasoula ◽

George Dranitsaris ◽

Amalia Vassou ◽

Justin Stebbing ◽

...

Keyword(s):

Multiple Myeloma ◽

Cpg Island ◽

Performance Status ◽

Methylation Status ◽

Cpg Methylation ◽

Epigenetic Silencing ◽

Refractory Disease ◽

Ecog Performance Status ◽

Beta 2 ◽

Beta 2 Microglobulin

Abstract Abstract 2397 Poster Board II-374 Background-Aim: BIK (bcl2-interacting killer) is the founding member of the BH3-only family proapoptotic proteins and is implicated in the selection of B cells in humans. The expression of BIK in cancer is prevented by chromosomal deletions or by epigenetic silencing. On the other hand, BIK upregulation is induced by proteasome inhibitors such as bortezomib and MG132. Although it has been shown that BIK is a target of epigenetic silencing in the IL-6 dependent multiple myeloma cell line KAS-6/1, no studies exist regarding the CpG methylation status of BIK in primary tumors. We wished to examine the CpG methylation status of BIK in patients with multiple myeloma (MM). Patients and methods: Bone marrow aspirate samples from individuals with MM were obtained at diagnosis. Methylation-specific PCR (MSP) was employed to study methylation in the BIK CpG island. Genomic DNA was isolated and bisulphite modification performed using commercially available kits (QIAmp DNA mini kit, Qiagen and EZ DNA methylation kit, ZymoResearch respectively). Control methylated (CpG GenomeTM Universal Methylated, Chemicon International) and unmethylated genomic DNAs were included in each experiment. Ten bone marrow samples from individuals with borderline thrombocytopenia, that proved to have no haematological malignancy, served as negative controls. Logistic regression analyses were used to measure the association between gene methylation and age, ISS stage, ECOG performance status, extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels and relapsed/refractory disease. Results: Methylation in the BIK CpG island was studied in 40 MM patients (21 male, 19 female, mean age 66). ISS staging were as follows: stage I 14 patients (36%), II 12 patients (31%), III 12 patients (31%). Methylation of the BIK CpG island was founded in 16 patients (40%) and men were more likely to be methylated (OR=3.08, p=0.098). No correlation was found between BIK CpG methylation and age, ECOG performance status, ISS staging, anemia, beta 2 microglobulin levels, albumin levels, and overall survival. Patients methylated for BIK had a 2-fold tendency to have bone disease (p=0.35) and a 3-fold tendency to have extramedullary disease (p=0.14). Notable, patients with methylated BIK had a higher risk of relapsed/refractory disease (OR=5.4, p=0.033). Conclusions: To the best of our knowledge, this is the first demonstration of aberrant methylation in the BIK CpG island in MM patients. Interesting associations between BIK CpG methylation and some relevant clinical parameters in patients with MM were suggested by the data. Most importantly, BIK CpG methylation in this series of patients was found to be strongly associated with relapsed/refractory disease. These findings warrant further evaluation in a larger sample of patients in order to better define the prognostic and clinical utility of BIK methylation in MM. Patients with refractory/relapsed disease could possibly benefit from agents enhancing BIK expression. Disclosures: No relevant conflicts of interest to declare.

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Genetic and Epigenetic Silencing of Mesoderm Specific Transcript (MEST) In Acute Myelogenous Leukemia.

Blood ◽

10.1182/blood.v116.21.3639.3639 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3639-3639

Author(s):

Anna R Poetsch ◽

Rainer Claus ◽

Lars Bullinger ◽

Tania Witte ◽

Michael LÃ¼bbert ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Cpg Island ◽

Normal Karyotype ◽

Epigenetic Silencing ◽

Myelogenous Leukemia ◽

Chromosome 7 ◽

Special Importance ◽

Monosomy 7 ◽

Chromosomal Changes

Abstract Abstract 3639 About 10 % of patients with either myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) present either with deletions on the long arm of chromosome 7 or monosomy 7. These chromosomal aberrations are associated with a poor prognosis. Following biallelic inactivation as proposed by Knudsen, a “second hit” of the remaining allele might be required for loss of gene function. Epigenetic silencing might display such a hit in particular since no additional genetic hits could be identified so far. The role of epigenetic regulation might be of special importance in patients with -7/7q-, since several studies have shown that patients harbouring a chromosome 7 abberrations do more benefit from a therapy with demethylating agents as compared to patients with other chromosomal changes. To address the issue of epigenetic silencing in these AML cases we utilized DNA methylation profiling to identify the potential tumor suppressor genes on chromosome 7. We used MBD2 based enrichment of methylated DNA from 4 AML patient samples with monosomy 7 and from 23 patient samples with with other chromosomal changes including normal karyotype AML. For validation we analyzed regional DNA methylation using quantitative MassArray technology on DNA from 115 del(7q) AML or monosomy 7 patients as well as normal karyotype patients (n=20) and CD34 + cells from healthy individuals (n=5). We could identify the gene MEST to be silenced by hypermethylation (> 30 %) of a CpG island on the remaining allele in 20% of the patients with -7/7q- and 40% of patients with normal karyotype. Thus, preferentially in patients that do not have a deletion already. MEST is an imprinted gene located on 7q32.2. However, silencing is correlated with hypermethylation of a CpG island located at an alternative promoter of MEST, independent of the methylation status of the imprinting control region. In two patient samples with monosomy 7 and hypermethylation of MEST (> 80%), DNA methylation was erased after 5-Aza-2′-deoxycytidine (DAC) treatment to less than 10 %. In concordance, also AML cell lines with hypermethylation of the MEST locus loose methylation after sublethal DAC treatment which leads to a reexpression of the gene. Thus, we hypothesize that MEST functions as a tumor suppressor in AML and is genetically as well as epigenetically silenced AML. Reactivation of MEST by demethylating treatment may contribute to the mechanism by which demethylating drugs display their therapeutic potential in leukemia. Disclosures: No relevant conflicts of interest to declare.

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