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CDKN2A, SMAD4, ARID1A, SPG20, TLR4, ELMO1 Comparison of cancer-associated genetic abnormalities in
and DOCK2 are signifi cantly mutated in EAC. p16 INK4a , the columnar-lined esophagus, with and without goblet
encoded by CDKN2A, inhibits CDK4 and 6 that bind cells, has revealed frequent copy number abnormalities
to cyclin D1 and blocks abnormal cell growth and in intestinal metaplasia, whereas no such changes were
proliferation. SMAD4 is a key intracellular mediator of observed in nongoblet cell metaplasia. [53]
[41]
transforming growth factor-beta signaling and is known Epigenetic alterations
[42]
to act as a tumor suppressor. ARID1A, which is one
of the chromatin remodeling genes, is frequently mutated The promoter hypermethylation of several tumor
[43]
in a variety of human cancers. Among the remaining suppressor genes, such as APC, CDKN2A, CDH1, FHIT,
four newly identifi ed genes, ELMO1 and DOCK2 are RARB, Ras-association domain family 1 (RASSF1),
upstream modulators of RAC1 GTPase, suggesting the MGMT, MLH1, and MSH2, causes decreased
potential activation of the RAC1 pathway as a contributor expression of these genes and has been known to affect
[54]
to EAC tumorigenesis. [36] carcinogenesis of ESCC [Table 4]. E-cadherin, encoded
by CDH1, is a calcium-dependent adhesion molecule that
Recently, comparison of mutated genes among NDBE, plays a crucial role in the maintenance of intercellular
HGD, and EAC revealed the majority of recurrently junctions in normal epithelial cells. The RARB gene
[55]
mutated genes in EAC, except TP53 and SMAD4, encodes retinoic acid receptor beta, a central regulator
were also mutated in NDBE. Mutations of TP53 and to normal growth and differentiation of a variety of
[44]
SMAD4 were stage-specifi c, confi ned to HGD and EAC, epithelial cells. The RASSF1 encodes a protein
[56]
respectively. [44]
similar to RAS effector proteins. RASSF1A protein
DNA copy number alterations modulates a broad range of cellular functions essential
[57]
for normal growth control. The MGMT gene encodes
Clustered abnormality in copy number was observed in O -methyl-guanine-DNA methyltransferase, a DNA repair
6
several genes in ESCC [Table 3], whereas a few genes
were specifi cally altered at high frequency in EAC.
[45]
Instead, EAC samples demonstrated more widespread Table 3: Representative amplifi ed or deleted genes in
squamous cell carcinoma of the esophagus
genomic instability and the total DNA copy number
alterations were an independent prognostic factor. [45] Genes Location Function
Amplifi cation
Amplifi cation and LOH observed in ESCC CCND1 11q13 Cell cycle progression
are summarized in Table 3. Amplifi cation and FGFR1 8p11 Mitogenesis, differentiation
overexpression of CCND1, which positively regulates EGFR 7p12 Proliferation
G1/S transition, are frequently observed. The PIK3CA 3q26 Cell growth, survival, proliferation
[46]
PI3K/AKT pathway is activated by amplifi cation and MYC 8q24 Cell cycle progression,
overexpression of receptor tyrosine kinases (fi broblast transformation
growth factor receptor 1 and epidermal growth factor SOX2 3q26 Stemness
receptor), KRAS, and PIK3CA. The transcriptional KRAS 12p12 Proliferation
[35]
genes MYC and SOX2 are occasionally amplifi ed. Loss of
Deletion of several tumor suppressor genes, including heterozygosity
TP53, adenomatous polyposis coli (APC), CDKN2A, TP53 17q13 Cell cycle arrest, DNA repair,
and FHIT, is observed in ESCC. APC suppresses apoptosis
canonical Wnt signaling through inhibition of -catenin, APC 5q21 Antagonist of Wnt signaling pathway
while it plays roles in several other fundamental CDKN2A 9p21 Cell cycle arrest
cellular processes such as cell adhesion, migration, and FHIT 3p14 Purine metabolism
chromosome segregation. Loss of FHIT transcripts
[47]
affects development and progression of various types Table 4: Representative hypermethylated genes in
of cancers. Loss of FHIT expression was reported esophageal cancer
[48]
to be associated with exposure to environmental Squamous cell carcinoma Adenocarcinoma
carcinogens. [49,50] APC APC
Amplifi cation/overexpression of ERBB2 (also known CDKN2A TIMP3
as human epidermal growth-factor receptor 2/neu) CDH1 CDKN2A
gene has been observed in 24-32% of esophagogastric FHIT CDH1
[51]
junction AC. The positive rate in EAC has been RARB MGMT
reported to be higher than that observed in gastric RASSF1 DAPK
[51]
cancer. Trastuzumab, an antibody to ERBB2, added to MGMT FHIT
chemotherapy, improved survival in patients with HER-2 MLH1 AKAP12
positive advanced gastric or gastroesophageal junction MSH2 SOCS-3
AC compared with chemotherapy alone. [52] Bold: Genes commonly hypermethylated in both subtypes

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