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Matsuoka et al. J Cancer Metastasis Treat 2018;4:6 I http://dx.doi.org/10.20517/2394-4722.2017.85 Page 5 of 13

[43]
highly expressed than that of other markers . Although the rate of expression differs in accordance with
subtype, expressions of at least one of MAGE-4, MAGE-6, MAGE-8, MAGE-9, MAGE-10, and MAGE-12
[44]
genes were as high as 82% in gastric cancerous specimen . Furthermore, previous studies reported that
MAGE was not expressed in normal gastric tissue . These results suggest that MAGE has been a candidate
[44]
as a novel targeted gene for the prediction of survival in patients with gastric cancer, and is expected to be a
therapeutic target due to its specific expression. A recent report in trial comparing the two markers CEA and
MAGE demonstrated that superior specificity and important association with peritoneal metastasis were
revealed in MAGE RT-PCR than in CEA RT-PCR after long-term follow-up, and MAGE RT-PCR results
were shown to be the most significant survival factor for peritoneal relapse in patients with gastric cancer
after curative surgical procedure .
[43]

Gene methylation
To identify micrometastasis in salivary rinses for head-and-neck cancer patients and pleural effusion for
several cancers, cancer-specific gene methylation has been commonly investigated. Thus, aberrant gene
methylation in PLF may predict peritoneal recurrence in gastric cancer. A previous study evaluated whether
methylation in the PLF by quantitative methylation-specific PCR analysis affects peritoneal metastasis after
surgery in the patients in which the depth of invasion of the primary lesion was beyond the muscularis
propria . Twelve-fold enhanced risk of peritoneal relapse in patients with positive methylation was shown
[45]
compared with in those with negative methylation by the combined assessment of the 6 genes (BNIP3, CHFR,
CYP1B1, MINT25, RASSF2, and SFRP2). Additionally, positive methylation rate in patients with peritoneal
metastasis or positive PLC was increased up to 75% by the combined assessment of the 6 genes, whereas
the rate in gastric cancer patients with the depth of cancer invasion beyond the muscularis propria (that
is, tumor involves the subserosa, tumor penetrates the serosa, and tumor invasion of adjacent structures
present) was 20%.

Exosomal miRNAs
MicroRNAs (miRNAs) are small non-coding RNAs that serve as posttranscriptional regulators of gene
expression and have an essential role in the control of many biological processes . A recent study
[46]
investigated the diagnostic potential of exosomal miRNA profiles in peritoneal fluid for the prediction of
peritoneal dissemination in gastric cancer . The miRNA content of exosomes isolated from malignant
[47]
ascites and peritoneal lavage fluid of gastric cancer patients was examined by miRNA microarray technology.
Significant high expressions of miR-21 and miR-1225-5p were found in patients with T4-stage cancer than
that in T1- to T3-stage patients, suggesting that profiling of miRNAs in peritoneal lavage fluid may be used
for the prediction of a peritoneal premetastatic phenotype in gastric cancer and may provide more effective
preventive and curative measures.

FBXO50
F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein E3 ligase
complexes, play essential roles in a variety of cellular processes through ubiquitylation which lead to the
degradation of target proteins . F-box only proteins (FBXOs) are key subclass of F-box proteins organized
[48]
in accordance with the existence of specific substrate recognition domains. Expression levels of FBXO50
mRNA in gastric cancer tissues from 200 patients were investigated, and the level of FBXO50 expression was
significantly correlated with positive peritoneal lavage cytology . FBXO50 would be another new candidate
[49]
tool of PLC for detecting micrometastasis in gastric cancer.

Other genetic markers
Besides the markers described above, numerous different markers to detect micrometastasis including
various aspects of biological activity in gastric cancer are known. The genetic alteration of proteinases,