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Review

Risk factors and molecular mechanisms of esophageal cancer:
differences between the histologic subtypes

Masayuki Watanabe
Department of Gastroenterological Surgery, Esophageal Cancer Division, Cancer Institute Hospital of Japanese Foundation for Cancer Research,
Tokyo 1358550, Japan.
Correspondence to: Dr. Masayuki Watanabe, Department of Gastroenterological Surgery, Esophageal Cancer Division, Cancer Institute Hospital of
Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 1358550, Japan. E-mail: masayuki.watanabe@jfcr.or.jp

ABSTRACT
The two major histologic subtypes of esophageal cancer have different risk factors as well as different molecular mechanisms. In
this review, the differences in risk factors and genetic/epigenetic alterations between esophageal squamous cell carcinoma (ESCC)
and esophageal adenocarcinoma (EAC) will be discussed. Cigarette smoking and alcohol consumption are risk factors for ESCC,
while gastroesophageal refl ux, cigarette smoking, and obesity are the main EAC risk factors. Commonly mutated genes of both
subtypes are TP53 and PIK3CA. Recent genome-wide analysis revealed that the activation of the RAC1 pathway may contribute
to EAC tumorigenesis. Clustered abnormality in copy number was observed in several genes in ESCC, whereas a few genes were
specifi cally altered at high frequency in EAC. Epigenetic changes, such as DNA methylation, histone modifi cations, and altered
expression of microRNAs, have been revealed to infl uence carcinogenesis and progression of both ESCC and EAC.
Key words: Epigenetic alterations, esophageal cancer, genetic alterations, risk factors

Introduction sequence. It has become evident that molecular
mechanisms also differ greatly between the two
Esophageal cancer affects more than 450,000 people histologic subtypes.
every year worldwide and is the 6th leading cause of
[1]
cancer-related mortality. The two major histologic In this review, the differences in both risk factors and
[2]
subtypes of esophageal cancer are esophageal molecular mechanisms between ESCC and EAC will be
squamous cell carcinoma (ESCC) and esophageal summarized.
adenocarcinoma (EAC). ESCCs are by far more common
in South East and Central Asia (79% of the total global Risk Factors
ESCC cases), while the highest number of EAC is There are different risk factors between ESCC and EAC.
found in Northern and Western Europe, North America Demonstrated in Table 1 are the major risk factors for
and Oceania (46% of the total global AC cases). The each histologic subtype.
[3]
remarkable variations in geographic distribution indicate
that different environmental risk factors likely affect the Both cigarette smoking and alcohol consumption are
[4,5]
occurrence of esophageal cancer. well-established risk factors for ESCC, with the risk in
heavy smokers/drinkers being 50 times greater than those
Recent progress in molecular biology has revealed that who neither drank nor smoked. Recently, defi ciency
[6]
several genetic and epigenetic alterations are implicated in the enzyme aldehyde dehydrogenase 2 (ALDH2),
in both carcinogenesis and progression of esophageal which causes so-called alcohol fl ushing response, has
cancer. Genetic alterations include a chromosomal loss been revealed to increase the risk of alcohol-related
or gain, loss of heterozygosity (LOH), and amplifi cation ESCC. In East Asian populations, there is a variant of
[7]
or mutations of genes. Epigenetic changes, such as ALDH2, resulting from the replacement of glutamate at
DNA methylation, histone modifi cations, and altered position 487 with lysine, with the lysine allele encoding
expression of microRNAs regulate gene expression an inactive protein. Drinking hot beverages may also
[8]
through mechanisms other than changes in DNA increase the risk of ESCC. In addition, patients with
[9]
achalasia are at markedly increased risk of developing
Access this article online ESCC, while both ESCC and EAC may develop as a
[10]
[11]
Quick Response Code: late complication of caustic injury. Oncogenic human
Website: papillomaviruses may increase the risk of ESCC, but the
www.jcmtjournal.com
evidence is inconclusive. [12]
Gastroesophageal refl ux disease (GERD), cigarette
DOI:
[13]
10.4103/2394-4722.153534 smoking, and obesity are the main EAC risk factors.
At least weekly symptoms of GERD increases the odds
Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦ 1