ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
Troponin I2 as a Speciﬁc Biomarker for Prediction of Peritoneal
Metastasis in Gastric Cancer
Koichi Sawaki, MD, Mitsuro Kanda, MD, PhD, FACS, Takashi Miwa, MD, Shinichi Umeda, MD,
Haruyoshi Tanaka, MD, Chie Tanaka, MD, PhD, Daisuke Kobayashi, MD, PhD, Masaya Suenaga, MD, PhD,
Norifumi Hattori, MD, PhD, Masamichi Hayashi, MD, PhD, Suguru Yamada, MD, PhD, FACS, Goro Nakayama,
MD, PhD, Michitaka Fujiwara, MD, PhD, and Yasuhiro Kodera, MD, PhD, FACS
Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
Background. Although peritoneal metastasis is a serious
concern in patients with gastric cancer, no acceptable and
speciﬁc biomarker is available. We aimed to identify a
candidate biomarker to predict peritoneal metastasis of
Methods. Metastatic pathway-speciﬁc transcriptome
analysis was conducted by comparison of patient groups
with no recurrence and with peritoneal, hepatic, and nodal
recurrence. Fifteen cell lines and 262 pairs of surgically
resected gastric tissues were subjected to messenger RNA
(mRNA) expression analysis. Polymerase chain reaction
array analysis was performed to explore coordinately
expressed cancer-related genes. To evaluate the in situ
protein localization and expression patterns, immunohis-
tochemical staining was performed.
Results. From transcriptome data, troponin I2 (TNNI2)
was identiﬁed as a candidate molecule speciﬁcally over-
expressed in gastric cancer prone to peritoneal metastasis.
TNNI2 mRNA was expressed at differential levels, inde-
pendent of differentiated phenotype of cell lines. Epithelial
to mesenchymal transition-related genes, tumor inhibitor of
metalloproteinase 1 (TIMP1), and vacuolar protein sorting
13 homolog A (VPS13A) were expressed with TNNI2 at
correlation coefﬁcient [ 0.7. The optimal cutoff of TNNI2
expression was determined as 0.00017. High TNNI2
expression was signiﬁcantly and speciﬁcally associated
with peritoneal metastasis and served as an independent
risk marker for peritoneal recurrence after curative gas-
trectomy. Prevalence of peritoneal recurrence increased in
parallel with staining intensity of TNNI2.
Conclusions. TNNI2 expression in gastric tissues may
serve as a speciﬁc biomarker for prediction of peritoneal
metastasis of gastric cancer and contribute to improvement
of patient management.
Peritoneal metastasis has been recognized as the most
critical factor in assessing prognosis of patients with gastric
cancer, and many efforts have been made to treat this
condition, with limited success.
Peritoneal recurrence is
frequently observed even after curative resection followed
by adjuvant therapy, because intraabdominal micrometas-
tasis is invisible and therapy resistant.
biomarkers that accurately diagnose or predict peritoneal
metastasis of gastric cancer help physicians in early
detection and prevention of this disease. To date, however,
no such biomarker for peritoneal metastasis is available.
The heterogeneity of gastric cancer presents an obstacle
in deﬁning molecular pathogenesis and developing sensi-
To metastasize to distant organs, cancer
cells exploit three major routes of dissemination: blood
vessels, lymphatic vessels, and direct seeding into the
Formation of peritoneal metastasis
comprises several steps: penetration of the gastric wall,
detachment of cancer cells from the primary tumor, sur-
vival in the microenvironment of the abdominal cavity,
attachment to the distant peritoneum, invasion of the sub-
peritoneal space, and proliferation with angiogenesis.
Electronic supplementary material The online version of this
article (https://doi.org/10.1245/s10434-018-6480-z) contains
supplementary material, which is available to authorized users.
Ó Society of Surgical Oncology 2018
First Received: 11 January 2018;
Published Online: 16 April 2018
M. Kanda, MD, PhD, FACS
Ann Surg Oncol (2018) 25:2083–2090