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of EAC fi ve-fold, while daily symptoms increased the 3-5 years has been recommended, and endoscopic eradication
odds seven-fold, when compared with those with less therapy is the treatment of choice for those with high-grade
[14]
[33]
frequent episodes. The relative risk of esophageal dysplasia (HGD). Recently, however, lengthening
and gastric cardia AC was 2.32 for current smokers and surveillance or discontinuing surveillance of patients with
[15]
1.62 for ex-smokers, as compared with never-smokers. persistent non-dysplastic Barrett’s esophagus (NDBE) has
However, a meta-analysis provided defi nite evidence of been discussed because of an annual cancer incidence of
an absence of association between alcohol drinking and only 0.1-0.3% in such patients. [34]
esophageal and gastric cardia AC risk. A systematic
[16]
review and meta-analysis revealed a high body mass Molecular Mechanisms
index (BMI) to be associated with a summary odds ratio Mutations
for gastroesophageal AC of 1.5. A recent prospective
[17]
cohort study in the United States found that a BMI Recently, the results of whole-exome or whole-genome
[35]
≥ 35 was associated with a hazard ratio of 3.67 compared sequencing to identify somatic mutations in ESCC and
[36]
with those with a normal-range BMI. Obesity may EAC have been reported. The frequently mutated genes
[18]
predispose to refl ux through mechanical means, while in esophageal cancers are shown in Table 2. The commonly
adipokines and cytokines secreted from adipocytes mutated genes of both subtypes are TP53 and PIK3CA. TP53
and infl ammatory cells are known to infl uence tumor is a major tumor-suppressor gene, its primary function being
[37]
[19]
development. Helicobacter pylori infection has been maintenance of genetic stability and DNA repair capacity.
[20]
reported to actually decrease the risk of EAC by 41% PIK3CA is a kinase activator of the phosphoinositide
through gastric atrophy, which leads to acid reduction. 3-kinase (PI3K)/AKT pathway and is frequently mutated
[39]
[38]
in many types of human cancers, including ESCC.
Radiotherapy for thoracic diseases, such as breast NOTCH1, FAT1, FAT2, KMT2D and ZNF750 are also
cancer and Hodgkin’s lymphoma, increases the risk of signifi cantly mutated in ESCC. NOTCH1 encodes one
both ESCC and EAC. [21,22] The incidence of both ESCC of the notch family receptors, and the notch signaling is a
and EAC increases with age. There is a strong male key pathway of the stem cell signaling network. There
[40]
predominance with up to eight men/one woman for EAC are other recently identifi ed mutated genes and the much
[35]
and three men/one woman for ESCC. [23,24] Fat distribution about the functions remains to be researched.
in obese men is predominantly abdominal, and increasing
abdominal diameter has been associated with an increased Table 1: Risk factors of esophageal cancer
[25]
EAC risk. However, the male predominance of ESCC Squamous cell carcinoma Adenocarcinoma
can be explained by the prevalence of smoking and Cigarette smoking Gastro-esophageal refl ux disease
alcohol drinking among males. Although an inhibitory Alcohol drinking Barrett’s esophagus
[26]
effect of estrogen in the growth of esophageal cancer ALDH2 defi ciency Refl ux symptoms
cells has been reported, there is no fi rm conclusion on the Drinking very hot liquids Obesity
role of estrogen in human esophageal cancer etiology. Achalasia Cigarette smoking
[27]
The familial form of ESCC is rare, although familial Caustic injury Diet (high in processed meat,
aggregation has been reported in a high incidence area low in fruits, vegetables)
[28]
in China. In contrast, familial clustering of Barrett’s History of thoracic radiation History of thoracic radiation
esophagus and EAC has been observed. In a European Tylosis Anticholinergic agents
cohort study, 7% of cases of Barrett’s esophagus and Human papilloma virus Family history
EAC were familial. [29] infection
N-nitrosamines Helicobacter pylori infection
The effi cacy of endoscopic surveillance for high-risk (decreased risk)
individuals is controversial. Both lugol chromoendoscopy
and an innovative optical image-enhanced technology
such as the narrow band imaging have been reported to be Table 2: Representative mutated genes in esophageal cancer
useful in detecting early ESCC. [30,31] In addition, endoscopic Squamous cell carcinoma Adenocarcinoma
esophageal surveillance has been recommended for TP53 TP53
newly-diagnosed head and neck cancer patients. However, KMT2D CDKN2A
[32]
there is no study evaluating the effi cacy of endoscopic FAT1 SMAD4
surveillance or screening among people heavily exposed FAT2 ARID1A
to ESCC risk factors. In contrast, endoscopic screening NOTCH1 PIK3CA
is recommended for patients with multiple risk factors in ZNF750 SPG20
Barrett’s esophagus, although there is no randomized clinical PIK3CA TLR4
trial that has shown effi cacy in preventing deaths due to ELMO1
esophageal cancer. For patients with Barrett’s esophagus DOCK2
[33]
without dysplasia, endoscopic surveillance at intervals of Bold: Genes commonly mutated in both subtypes

2 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦