Page 77 - Read Online

In fact, many exciting discoveries in epigenetics have esophagectomy. Ling et al. showed that MSH2
[17]
[16]
emerged from the study of gastrointestinal (GI) cancers. promoter hypermethylation in circulating tumor DNA
In this review, we summarized the accumulated evidence was a valuable predictor of disease-free survival of ESCC
supporting the clinical application of DNA methylation patients after esophagectomy. Aberrant methylation of
level in diagnosis of esophageal, gastric and colorectal FHIT was also reported to be associated with exposure to
cancers. tobacco smoking and individuals with early-stage ESCC
whose tumors exhibited FHIT hypermethylation had poor
Altered DNA Methylation in Esophageal Cancer prognoses. CDH1 hypermethylation was detected in
[18]
Esophageal cancer can be classifi ed into two histological 14-61% of ESCC, which was associated with recurrence
[19]
types, esophageal squamous cell carcinoma (ESCC) and of early-stage ESCC. Moreover, aberrantly methylated
esophageal adenocarcinoma ( EAC). Their incidences gene promoters were also detected in plasma or sera of
[20]
vary notably by geographic distribution. ESCC accounts ESCC patients. Hibi et al. showed that p16 promoter
for approximately 90% of the esophageal cancers in methylation in ESCC specimens had this same methylation
East Asian countries, [10,11] whereas the highest number of change in their serum DNA in 23% the of patients, which
EAC is found in Northern and Western Europe, North implied that detection of serum DNA p16 promoter
America and Oceania. These two subtypes also have methylation could serve as a tumor marker. However, few
[12]
different epigenetic alterations. Growing evidence suggests studies have addressed or detected DNA hypo-methylation
that there is a fi eld of epigenetic changes in esophageal in ESCC. LINE-1 methylation is regarded as a surrogate
cancer [13-15] by particularly emphasized signifi cance of marker for global DNA methylation. To better understand
promoter hypermethylation of 14 specifi c genes (SFRP1, DNA methylation in ESCC tissues, our group measured
SFRP2, DCC, APC, p16, p14, APBA1, APBA2, APBA3, their LINE-1 methylation using the pyrosequencing
CACNA1G, PTGS2, DAPK1, MLH1 and MGMT) in technology. Chronic tobacco smoking and heavy
non-cancerous mucosae from ESCC patients vs. mucosae alcohol drinking are established as risk factors for
from healthy volunteers, indicating that aberrant ESCC development. [21-25] LINE-1 hypo-methylation is
[13]
methylation or these 14 gene promoters in esophageal signifi cantly associated with tobacco smoking, which
mucosae is associated with ESCC development. An supports its plausibility as a surrogate marker for an
[26]
overview of different previous studies of clinical epigenetic fi eld defect. LINE-1 methylation is highly
implications of DNA methylation in esophageal cancer variable among ESCC specimens (25-92%) and its
is provided in Table 1. Aberrant promoter methylation hypo-methylation is strongly associated with poor ESCC
of tumor suppressor genes has also been used to predict prognosis. Moreover, loss of insulin-like growth factor
[27]
clinical outcomes following curative ESCC resections. 2 (IGF2) imprinting has been found in ESCC and loss of
For example, promoter methylation of APC has been IGF2 methylation is associated with shorter survival of
associated with reduced survival of ESCC patients after patients. [28]

Table 1: Association of gene promoter methylation with clinical outcomes of esophageal cancer patients
Gene Histological type Correlation with clinical outcomes Reference
DNA hypermethylation
APC ESCC Associated with poor prognosis [16]
CDH1 ESCC Associated with poor prognosis [19]
p16 ESCC Associated with poor prognosis, serum promoter methylation [20,94]
Claudin-4 ESCC Associated with poor prognosis [95]
FHIT ESCC Associated with poor prognosis and tobacco/alcohol consumption [18,96]
Integrin α4 ESCC Associated with poor prognosis [19]
MGMT ESCC Association with lymph node metastasis [97]
MSH2 ESCC Associated with poor prognosis [17,98]
AKAP12 Barrett/BAC Progression prediction in Barrett’s esophagus [31]
CDH13 Barrett/BAC Progression prediction in Barrett’s esophagus [31]
p16 Barrett/BAC Progression prediction in Barrett’s esophagus [31,99]
HPP1 Barrett/BAC Progression prediction in Barrett’s esophagus [31,99]
NELL1 Barrett/BAC Progression prediction in Barrett’s esophagus [31]
RUNX3 Barrett/BAC Progression prediction in Barrett’s esophagus [31,99]
SST Barrett/BAC Progression prediction in Barrett’s esophagus [31]
TAC1 Barrett/BAC Progression prediction in Barrett’s esophagus [31]
DNA hypomethylation
IGF2 ESCC Associated with poor prognosis [28]
LINE-1 ESCC Associated with poor prognosis and tobacco consumption [26,27]
ESCC: Esophageal squamous cell carcinoma; Barrett/BAC: Barrett’s esophageal adenocarcinoma

114 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦