Age, DNA Methylation and the Malignant Potential of the Serrated Neoplasia Pathway

2021 ◽  
Author(s):  
◽  
Lochlan Fennell
Keyword(s):  
Dna Methylation ◽  
Malignant Potential ◽  
Serrated Neoplasia Pathway

Decitabine Induced the Cell Differentiation, Decreased Malignant Potential, and Increased Susceptibility to Apoptosis Via a Death Receptor Pathway with Hypomethylation of MS4A3, PAR-4, APITD1, LOX in Myelodysplastic Syndrome Cell Line, MDS-L

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4599-4599
Author(s):  
Rie Nishi ◽  
Takahiro Yamauchi ◽  
Miyuki Ookura ◽  
Yasufumi Matsuda ◽  
Toshiki Tasaki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Differentiation ◽  
Cell Line ◽  
Wilms Tumor ◽  
Methylation Status ◽  
Death Receptor ◽  
Malignant Potential ◽  
Methylation Array ◽  
L Cells ◽  
Dna Methylation Array

Abstract Introduction: Myelodysplastic syndrome (MDS) is a group of clonal myeloid disorders characterized by ineffective hematopoiesis and cytopenias. Treatment strategies are based on the balance between patients’ predicted lifespan and the anticipated risk-benefit of intervention. Current guidelines recommend to classify patients into low-risk and high-risk groups. Hypomethylating agents azacitidine and decitabine are recommended for patients with high-risk MDS, who are not eligible for intensive therapy including stem cell transplantation. Azacitidine showed a survival benefit, however, treatment with this agent has not been standardized. To further optimize the use of hypomethylating agents, the target molecules of the agents should be identified to select patients, who would best benefit from the hypomethylating treatment. In the present study, the cellular drug sensitivity, the cell differentiation, the induction of apoptosis, and DNA methylation status after the treatment with decitabine were extensively investigated using cultured MDS cell line MDS-L that had been previously established. Methods: MDS-L cells, which had been established in the previous study (Br J Haematol, 87,235-242,1994) were used. This cell line is a blastic subline derived from the bone marrow blasts of a 50-year Japanese male patients with MDS. Trypan dye exclusion assay was used for determining growth inhibition effects. The cellular morphology was observed by staining the cells with May- Grunwald-Giemsa dye. Cell surface markers were detected by using flow cytometry. The transcript of Wilms’ tumor 1 was measured by real time RT-PCR. The induction of apoptosis was determined either by the sub-G1 population in the cell cycle analysis or the caspase cleavage. The enzymatic activity of DNA methyltransferase 1 (DNMT1) was determined by using a DNMT1 activity assay kit (Active Motif, Carlsbad, CA). DNA methylation array was performed using Infinium Human Methylation 450 BeadChip (Illumina, San Diego, CA). Results: The 50%-growth inhibitory concentration of decitabine was 64 nM in MDS-L cells. The cells were incubated with a non-toxic concentration (5 nM) of decitabine for 6 months (named as MDS-L-DAC cell line). MDS-L-DAC cells proliferated more slowly than untreated MDS-L cells (doubling time:51 h). Morphologically, MDS-L-DAC cells were maturated with a lobulated nuclei and cytoplasmic granulation. Differentiation induction was also indicated by an increased CD15 positivity (9.3→30.5%) and a decreased CD34 positivity (98.8→6.4%) in MDS-L-DAC cells. Wilms’ tumor 1 transcript level was also reduced (1,400,000→420,000 copies/μgRNA) in MDS-L-DAC cells, suggesting a decreased malignant potential by the effect of decitabine. Decitabine induced greater amount apoptosis (sub-G1 :12.3%) was with caspase 3 and caspase 8 cleavage in MDS-L-DAC cells, but not in MDS-L cells (sub-G1: 5.6%). The enzymatic activity of DNMT1 was successfully inhibited by decitabine in MDS-L-DAC cells (11.2→4.5OD/h/mg). The epigenome-wide association study using DNA methylation array compared the methylation status at CpG islands between MDS-L cells and MDS-L-DAC cells. Demethylation occurred in MS4A3 (Membrane-spanning 4-domains subfamily A member 3), PAR-4 (Prostate apoptosis response 4), CD40LG (CD40 ligand), APITD1 (Apoptosis-inducing, TAF 9-like domain 1), LOX (Lysyl Oxidase), and AMPH (Amphipysin) in MDS-L-DAC cells. Western blotting confirmed that the corresponding protein levels were increased. Discussion and Conclusions: MS4A3 is associated with myeloid differentiation. Caspase-8-mediated PAR-4 cleavage is required for tumor necrosis factor α-induced apoptosis. Low expression of APITD1 interferes with the ability for apoptosis through the p53 pathway. LOX is one of the commonly methylated genes in gastric cancer. Thus, the long-term incubation with decitabine at a low concentration demethylated these gene promoters and regained their protein expression. Decitabine induced the cell differentiation, decreased malignant potential, and increased susceptibility to apoptosis via a death receptor pathway, provably due to the functions of these proteins. Disclosures No relevant conflicts of interest to declare.

scholarly journals The serrated neoplasia pathway of colorectal tumors: Identification ofMUC5AChypomethylation as an early marker of polyps with malignant potential

2015 ◽  
Vol 138 (6) ◽  
pp. 1472-1481 ◽  
Author(s):  
Florence Renaud ◽  
Christophe Mariette ◽  
Audrey Vincent ◽  
Agnès Wacrenier ◽  
Vincent Maunoury ◽  
...  
Keyword(s):  
Malignant Potential ◽  
Colorectal Tumors ◽  
Early Marker ◽  
Serrated Neoplasia Pathway

Ultrastructure of Cryptorchidism and Seminoma

1981 ◽  
Vol 39 ◽  
pp. 540-541
Author(s):  
Shirley Siew ◽  
Susan C. James
Keyword(s):  
Malignant Tumors ◽  
Frozen Section ◽  
Malignant Potential ◽  
Genetic Influences ◽  
Endocrine Gland ◽  
Medial Aspect ◽  
Left Testis ◽  
Bilateral Orchiectomy

Testicular maldescent is the most common endocrine gland abnormality, as 2.7% of mature neonates are cryptorchid. The significant complications are that there is a disturbance of normal maturation which results in diminished fertility and there is an increase in the malignant potential which is 35 times greater in the undescended than the descended testis. It is considered that genetic influences may be of etiological importance and recurrence has been described in some families. It is of interest, that the case reported here has 2 siblings who have also presented with cryptorchidism and malignant tumors.The propositus is 14 years old. He is well developed (described by some as obese) and shows normal secondary male characteristics except for an immature scrotum. Laparotomy showed both testes to be intraabdominal. A hard nodule (0.5cm) was palpated on the medial aspect of the left testis. Frozen section showed the presence of seminoma and bilateral orchiectomy was performed.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma

2001 ◽  
Vol 120 (5) ◽  
pp. A558-A558
Author(s):  
M TAMANO ◽  
K KOJIMA ◽  
M OGUMA ◽  
M LIJIMA ◽  
T MUROHISA ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Malignant Potential ◽  
Small Hepatocellular Carcinoma

Castleman's Disease Masquerading as Sigmoid Colon Tumor and Hodgkin Lymphoma

Swiss Surgery ◽  
2002 ◽  
Vol 8 (1) ◽  
pp. 7-10 ◽  
Author(s):  
Altinli ◽  
Pekmezci ◽  
Balkan ◽  
Somay ◽  
M. Akif Buyukbese ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Sigmoid Colon ◽  
Castleman’S Disease ◽  
Malignant Potential ◽  
Colon Tumor ◽  
Rare Entity ◽  
Castleman's Disease ◽  
Mediastinal Lymph Nodes ◽  
Histologic Types

Castleman's disease is a benign lymphoid neoplasm first reported as hyperplasia of mediastinal lymph nodes. Some authors referred to the lesions as isolated tumors, described as a variant of Hodgkin's disease with a possibility of a malignant potential and others proposed that the lymphoid masses were of a hamartomatous nature. Three histologic variants and two clinical types of the disease have been described. The disease may occur in almost any area in which lymph nodes are normally found. The most common locations are thorax (63%), abdomen (11%) and axilla (4%). We report two separate histologic types of Castleman's disease which were rare in the literature, mimicking sigmoid colon tumor and Hodgkin lymphoma. The diagnostic and therapeutic aspects of this rare entity is discussed.

15 LONGITUDINAL EVALUATION OF MUCOSAL DNA METHYLATION IN ULCERATIVE COLITIS SHOWS DISEASE-SPECIFIC CHANGES

2020 ◽  
Vol 158 (3) ◽  
pp. S50-S51
Author(s):  
Suresh Venkateswaran ◽  
Varun Kilaru ◽  
Hari Somineni ◽  
Jason Matthews ◽  
Jeffrey Hyams ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Dna Methylation ◽  
Longitudinal Evaluation ◽  
Disease Specific
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