Cancer Res Treat.  2018 Oct;50(4):1351-1361. 10.4143/crt.2017.487.

Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer

• Yun S
• Kwak Y
• Nam SK
• Seo AN
• Oh HK
• Kim DW
• Kang SB
• Lee HS

• KMID: 2424807
• DOI: http://doi.org/10.4143/crt.2017.487

Abstract

PURPOSE
Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients' survival with CRC.
MATERIALS AND METHODS
The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH.
RESULTS
Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands-/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis.
CONCLUSION
Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.

Keyword

Colorectal neoplasms; Epidermal growth factor receptor; Ligands; mRNA in situ hybridization

MeSH Terms

Betacellulin
Colorectal Neoplasms*
Disease-Free Survival
Epidermal Growth Factor*
Heparin
Humans
Immunohistochemistry
In Situ Hybridization
Incidence
Ligands
Multivariate Analysis
Prognosis*
Receptor, Epidermal Growth Factor*
RNA, Messenger
Silver
Transforming Growth Factors
Betacellulin
Epidermal Growth Factor
Heparin
Ligands
RNA, Messenger
Receptor, Epidermal Growth Factor
Silver
Transforming Growth Factors

Figure

• 

  Fig. 1. Representative images of mRNA expression of epidermal growth factor receptor ligands in colorectal cancer. (A) Heparin binding epidermal growth factor–like growth factor (×400). (B) Transforming growth factor (×400). (C) Betacellulin (×400). (D) Epidermal growth factor (×400).

• 

  Fig. 2. Kaplan-Meier survival curves according to the combined expression status of ligands and epidermal growth factor receptor (EGFR). (A) Disease-free survival. (B) Overall survival.

Reference

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