Different clinical significance of FGFR1–4 expression between diffuse-type and intestinal-type gastric cancer
Inokuchi et al. World Journal of Surgical Oncology
Different clinical significance of FGFR1-4 expression between diffuse-type and intestinal-type gastric cancer
Mikito Inokuchi 0
Hideaki Murase 0
Sho Otsuki 0
Tatsuyuki Kawano 0
Kazuyuki Kojima 1
0 Department of Gastrointestinal Surgery, Tokyo Medical and Dental University , 1-5-45, Yushima, Bunkyo, Tokyo 113-8519 , Japan
1 Department of Minimally Invasive Surgery, Tokyo Medical and Dental University , 1-5-45, Yushima, Bunkyo, Tokyo 113-8519 , Japan
Background: Receptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1-4 expression separately in DGC and IGC. Methods: Tumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution. The expression levels of FGFR1, 2, 3, and 4 were measured in the tumors by immunohistochemical analysis. Results: In DGC, high expression of FGFR1, FGFR2, or FGFR4 was significantly associated with the depth of invasion, lymph-node metastasis, pathological stage, and distant metastasis or recurrent disease. Patients with high expression of FGFR1, FGFR2, or FGFR4 had significantly poorer disease-specific survival (DSS) (p = 0.009, p = 0.001, and p = 0.023, respectively). In IGC, only FGFR4 expression was significantly associated with factors relative to tumor progression and with shorter DSS (p = 0.012). Conclusion: In conclusion, high FGFR4 expression correlated with tumor progression and survival in both DGC and IGC, whereas high expression of FGFR1 and 2 correlated with tumor progression and survival in only DGC.
Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 2; Fibroblast growth factor receptor 3; Fibroblast growth factor receptor 4; Gastric cancer; Immunohistochemistry
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Background
Gastric cancer (GC) is categorized into three types based
on Lauren’s pathological classification: diffuse type,
intestinal type, and mixed type [1]. Diffuse-type gastric
cancer (DGC) is associated with more advanced
disease stage and poorer survival than intestinal-type
gastric cancer (IGC) [2, 3]. It is well known that
protein or gene overexpression of receptor tyrosine
kinases (RTKs) correlates with tumor progression and
poor survival in GC [4, 5]. The immunohistochemical
overexpression of human epidermal growth factor
receptor 2 (HER2), one of the RTKs, was detected
more frequently in IGC than in DGC [6]. Comprehensive
genomic analyses performed in The Genomic Cancer
Atlas (TGCA) project revealed different genomic
alterations of RTKs between DGC and IGC [7]. Therefore,
the impact of RTK overexpression on clinical outcomes
might differ between DGC and IGC.
The fibroblast growth factor receptor (FGFR) family
comprises one type of RTK that regulates fundamental
developmental pathways by interacting with fibroblast
growth factors (FGFs). FGF signaling participates in
several biological functions in the adult organism, including
regulation of angiogenesis and wound repair. FGFRs are
expressed on a number of different cell types and regulate
key cell activities, such as proliferation, survival, migration,
and differentiation [8]. FGFR2 gene amplification was
initially found in a GC cell line originating from DGC
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with the poorest prognosis [9]. Gene amplification or
protein overexpression of FGFR2 has been reported in
GC, leading to poor outcomes [10]. Moreover, GC cell
lines presenting with FGFR2 amplification are highly
sensitive to inhibition of FGFR signaling by tyrosine
kinase inhibitors and monoclonal antibodies in preclinical
models [11, 12]. FGFR2 has thus attracted considerable
attention as a novel therapeutic candidate for the
development of targeted anticancer agents [13].
We previously reported the relations of the
immunohistochemical expressions of FGFR1–4 to tumor
progression or poor survival in GC. However, tumors were
classified into differentiated and undifferentiated types
based on the World Health Organization pathological
classification in the previous study and were not
cl (...truncated)