Cancer Genetics and Epigenetics 2015, Vol.3, No.11, 1-8
2
as DNA methylation, histone modification [8].Causes
of acute myeloid leukemia include changes in
hematopoietic stem cell epigenetics, these changes
lead to the growth of hematopoietic stem cell
proliferation and changes in differentiation occur [6].
DNA methylation is a major epigenetic modification
process. DNA methylation have played an important
role in the development of disease cells and normal
cells [3, 9, 10].Periodic abnormal DNA methylation
patterns are commonly observed in cancer cells. It
means that epigenetic modification is associated with
the formation and development of cancer [4, 5, 11].
During cell division, DNA methylation involves in the
process of DNA synthesis new strands.
DNMT3A
and
DNMT3B can help to transfer the methylation process
[6].DNA methylation also involves in normal
hematopoietic development and it has an important
impact on the medullary tumors. Analysis of
methylation profiles in the specific genomic location
may affect the treatment of individual tumor subtypes
[12-14]. CpG island methylation phenomenon (CIMP)
is clinically used to distinguish cancer phenotypes
CpG island hypermethylation [15, 16]. Recently, some
genomic modification also affects the epigenetic
regulation, such as
IDH1
and
IDH2
genes in malignant
glioma,Tet2 genes in leukemia [17].
Currently, Mutations in the genetic sequence of
DNMT3A
are found in many patients with acute myeloid
leukemia. They lead to dysfunction of
DNMT3A
protein and bad prognosis [18-22].
DNMT3A
located
on chromosome 2p23, is highly expressed in some
tumors [6].
DNMT3A
mutations are associated with AML poor
prognosis, therefore suggests to take into account the
use of risk stratification [6].DNMT inhibitors have
been used in the treatment of myelodysplastic syndrome
and leukemia [6].However, DNMT inhibitors predict
biomarker for the management of other treatment
modalities is also unknown [6].
The study found that
IDH1
and
IDH2
mutations occur
frequently in AML patients [7]. Isocitrate dehydrogenase
is associated with cell metabolism, which can promote
isocitrate and α- ketoglutarate transformed into each
other in the cell, leading to DNA mutation and
regulation of histone [7].However, when the enzyme
of gene encoding mutations,
IDH
will converted α-
ketoglutarate to 2-hydroxyglutaric acid [23].Studies have
shown that 2-hydroxyglutaric acid can produce
antagonism, lower α- ketoglutarate dependent enzyme
activity, resulting in chromatin methylation and cancer
[7, 24].In addition, the citric acid cycle is essential for
many biochemical signaling pathways, one of the
important enzyme is isocitrate dehydrogenase [23].
1 Methods
1.1 Datasets
The AML clinical data were downloaded from
TCGA (
Cancer
Genome Atlas (TCGA) is coordinated by a project
team comprised of individuals from both the National
Cancer Institute and the National Human Genome
Research Institute and advised by an External Scientific
Committee whose membership includes patient
advocates, senior scientists and clinicians with relevant
expertise in cancer, genomics and ethics. JHU-USC
HumanMethylation450K data of 74 AML samples
downloaded from TCGA (42
DNMT3A
samples,19
IDH
samples and 13
IDH_3AD
samples), together with
40 normal samples DNA methylation data downloaded
from GEO with accession number of GSE35069;Gene
expression data of disease samples were downloaded
from TCGA (
) with WUSM
HG-U133_Plus_2 and standardized RMA. Gene
expression data of control samples were downloaded
from GEO (The Gene Expression Omnibus) with
accession number of GSE48060 (21 samples).Reference
genome from UCSC (This site contains the reference
sequence and working draft assemblies for a large
collection of genomes. It also provides portals to
ENCODE data at UCSC (2003 to 2012) and to the
Neandertal project).
DNMT3A
mutations were
recorded as
DNMT3A
,
IDH
mutations were recorded
as
IDH
,
DNMT3A
and
IDH
mutations in a sample
were recorded as
IDH_3AD
, normal samples were
recorded as control. The Gene Expression Omnibus (GEO)
repository at the National Center for Biotechnology
Information (NCBI) archives and freely disseminates
microarray and other forms of high-throughput data
generated by the scientific community.
1.2 DNA methylation data analysis
Firstly, the samples were divided into four groups with
DNMT3A
,
IDH
,
IDH_3AD
, control. After removing the
missing values, we screened DMS during the same
mutation and aimed at removing the difference
