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also plays an important role in intestinal differentiation with progression of BE to high-grade dysplasia or EAC.
in cell proliferation, apoptosis, and normal cell ARID1A is another key molecule driving BE to EAC.
[53]
differentiation. [42,43]
ARID1A is a member of SWI/SNF family of chromatin
SHH, BMP4, SOX9, and CDX2 are key molecules remodeling. This molecule has been examined mainly
for the development of intestinal metaplasia. SHH/ in gastric cancer and reported to be associated with
BMP4 axis, which is a key signaling for esophageal microsatellite instability. [54,55] ARID1A mutation
development, plays an important role in the intestinal was detected around 15% of BE with high-grade
metaplasia of BE. In addition, SNPs that are related to dysplasia and EAC. The frequency of loss of ARID1A
esophageal organogenesis, such as FOXF1 and FOXP3, by immunohistochemistry correlated with disease
are frequently observed in BE patients [Table 1]. progression from BE to EAC. The EAC cell line, OE33,
showed phenotypes of increased proliferation and
Genetic Alterations in Progression of BE to aggressive invasion, as the gastric cancer cell line also
EAC did. [53,54] In addition to ARID1A, the other members of
Few cases of BE will develop high-grade dysplasia or chromatin remodeling factors encoding genes, ARID2,
[56]
adenocarcinoma. The widely accepted molecular events and SMARC4A mutations, were also reported.
during progression of BE to adenocarcinoma are loss Rho family GTPase activation is an important molecule
of normal TP53 and CDKN2A function. Mechanisms in gastric cancer and EAC. Rho family consists of
underlying this have been explained by loss of Cdc2, Rac1, and RhoA. These molecules are master
heterozygosity (LOH), mutation, or promoter methylation. regulators of actin cytoskeleton rearrangements,
Tumor suppressor genes, TP53 and CDKN2A, are located promote cancer cell invasion, and cell survival. In
[44]
at 17p and 9p, respectively. 17p LOH occurs frequently gastric cancer, a mutation of RhoA is frequently
in EAC, [45-47] while TP53 mutation possesses malignant associated with diffuse-type gastric cancer. It has
[48]
transformation potential during EAC carcinogenesis. 9p been reported that mutations in ELMO1 and DOCK2
LOH has been reported to be the important factor driving are frequently noted in cases with EAC. These are
to EAC. Somatic mutation of CDKN2A has also been intracellular mediators of RAC1. ELMO1 and DOCK2
[44]
detected in EAC cases. In addition, tumors harboring promote tumor cell invasion and seem to be associated
[49]
promoter methylation in CDKN2A showed a higher risk of with EAC carcinogenesis. [57] It was observed that 6%
EAC progression. [50,51] Although 9p LOH is an earlier event of EAC cases analyzed had mutations in ELMO1 and
during EAC carcinogenesis compared to 17q LOH, patients 13% in DOCK2. Other genes encoding Rac1 activating
with BE harboring 9p LOH experienced much higher enzymes were ECT2 (1%), TIAM1 (3%), TRIO (3%)
incidence of EAC compared to those with 17q LOH. [44] and VAV2 (1%) although these frequencies were lower
than those in ELMO1 and DOCK2. Taken together,
Comprehensive genetic analysis has provided new
insights in the genetic landscape of BE-to-EAC. One around 30% of Rac1- activating mutations occurred
group has shown that most mutations in EAC had in EAC patients. Also reported in EAC were frequent
already occurred in matched BE, using comprehensive transversions of A to C at AA sites (T to G at TT
[56,58]
genetic analysis on 11 cases with EAC and 2 of BE. sites). One possible explanation was that low pH
Another group analyzed the mutations in selected 26 due to GERD induces 8-OH-dG, resulting in A to C
[59,60]
genes and reported that around half of the cases with transversion at AA sites. Further studies also needed
BE without dysplasia already possessed mutations. Also, to clarify this interesting fi nding.
there was no signifi cant difference in frequencies of Epigenetic Changes and microRNA Status in
those mutations between BE without dysplasia, BE with BE and EAC
[52]
high-grade dysplasia, and EAC. Of note, they also
examined associations between frequencies of mutations Recent global methylation profi ling revealed that broad
in the 26 genes and disease stage. They also found that epigenetic alterations occur in both BE and EAC and
only TP53 and SMAD4 mutations signifi cantly increased are associated with carcinogenesis in EAC. [61-64] CpG
island promoter hypermethylations are a common feature
of cancer, and regulate (traditionally down-regulate)
Table 1: Major molecular alterations reported across downstream gene expression. On the other hand, DNA
malignant progression of BE hypomethylation increases gene expression. As for
[62]
Morphological status Key molecular alterations specifi c CpG island promoter methylations, CDKN2A,
BE SHH, BMP4, SOX9 and CDX3
Esophageal adenocarcinoma Loss of function of CDKN2A or APC, CDH1, MGMT, TIMP-3 and ESR1 have
[51,65-68]
TP53 (by loss of heterozygosity, been evaluated in several reports. CDKN2A
or mutation); ARID1A, SMAD4 hypermethylation has been considered to occur in early
SHH: Sonic hedgehog; BE: Barrett’s esophagus; BMP: Bone steps in EAC carcinogenesis. One study suggested that 4
morphogenetic protein; SOX9: SRY (sex determining region Y) genes, SLC22A18, PIGR, GJA12 and RIN2, were highly
box 9 methylated in EAC compared to BE. [63]

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 125