Epidermal Growth Factor Receptor (EGFR) Is Overexpressed in High-Grade Dysplasia and Adenocarcinoma of the Esophagus and May Represent a Biomarker of Histological Progression in Barrett's Esophagus (BE)

被引:60
作者
Cronin, James [1 ]
McAdam, Elizabeth [1 ]
Danikas, Antonios [2 ]
Tselepis, Chris [3 ]
Griffiths, Paul [4 ]
Baxter, John [5 ]
Thomas, Linzi [6 ]
Manson, James [5 ]
Jenkins, Gareth [1 ]
机构
[1] Swansea Univ, Swansea Sch Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales
[2] GE Healthcare, Grove Ctr, Amersham, England
[3] Univ Birmingham, Sch Canc Studies, Birmingham, W Midlands, England
[4] ABM Trust, Morriston Hosp, Dept Histopathol, Swansea, W Glam, Wales
[5] ABM Trust, Morriston Hosp, Dept Surg, Swansea, W Glam, Wales
[6] ABM Trust, Singleton Hosp, Dept Gastroenterol, Swansea, W Glam, Wales
关键词
PROGNOSTIC-SIGNIFICANCE; CARCINOMA SEQUENCE; COLORECTAL-CANCER; GENE-EXPRESSION; CYCLIN D1; C-MYC; SURVIVAL; METAPLASIA; RISK; CHEMORADIOTHERAPY;
D O I
10.1038/ajg.2010.433
中图分类号
R57 [消化系及腹部疾病];
学科分类号
100201 [内科学];
摘要
OBJECTIVES: The assessment of cancer risk in patients with Barrett's esophagus (BE) is currently fraught with difficulty. The current gold standard method of assessing cancer risk is histological assessment, with the appearance of high-grade dysplasia (HGD) as the key event monitored. Sampling error during endoscopy limits the usefulness of this approach, and there has been much recent interest in supplementing histological assessment with molecular markers, which may aid in patient stratification. METHODS: No molecular marker has been yet validated to accurately correlate with esophageal histological progression. Here, we assessed the suitability of several membranous proteins as biomarkers by correlating their abundance with histological progression. In all, 107 patient samples, from 100 patients, were arranged on a tissue microarray (TMA) and represented the various stages of histological progression in BE. This TMA was probed with antibodies for eight receptor proteins (mostly membranous). RESULTS: Epidermal growth factor receptor (EGFR) staining was found to be the most promising biomarker identified with clear increases in staining accompanying histological progression. Further, immunohistochemistry was performed using the full-tissue sections from BE, HGD, and adenocarcinoma tissues, which confirmed the stepwise increase in EGFR abundance. Using a robust H-score analysis, EGFR abundance was shown to increase 13-fold in the adenocarcinoma tissues compared to the BE tissues. EGFR was "overexpressed" in 35% of HGD specimens and 80% of adenocarcinoma specimens when using the H-score of the BE patients (plus 3 s.d.) as the threshold to define overexpression. EGFR staining was also noted to be higher in BE tissues adjacent to HGD/adenocarcinoma. Western blotting, although showing more EGFR protein in the adenocarcinomas compared to the BE tissue, was highly variable. EGFR overexpression was accompanied by aneuploidy (gain) of chromosome 7, plus amplification of the EGFR locus. Finally, the bile acid deoxycholic acid (DCA) (at neutral and acidic pH) and acid alone was capable of upregulating EGFR mRNA in vitro, and in the case of neutral pH DCA, this was NF-kappa B dependent. CONCLUSIONS: EGFR is overexpressed during the histological progression in BE tissues and hence may be useful as a biomarker of histological progression. Furthermore, as EGFR is a membranous protein expressed on the luminal surface of the esophageal mucosa, it may also be a useful target for biopsy guidance during endoscopy.
引用
收藏
页码:46 / 56
页数:11
相关论文
共 41 条
[1]
NF-κB activation in Esophageal adenocarcinoma -: Relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy [J].
Abdel-Latif, MMM ;
O'Riordan, J ;
Windle, HJ ;
Carton, E ;
Ravi, N ;
Kelleher, D ;
Reynolds, JV .
ANNALS OF SURGERY, 2004, 239 (04) :491-500
[2]
Immunohistochemical studies on EGF family growth factors in normal and ulcerated human gastric mucosa [J].
Abe, S ;
Sasano, H ;
Katoh, K ;
Ohara, S ;
Arikawa, T ;
Noguchi, T ;
Asaki, S ;
Yasui, W ;
Tahara, E ;
Nagura, H ;
Toyota, T .
DIGESTIVE DISEASES AND SCIENCES, 1997, 42 (06) :1199-1209
[3]
AMPLIFICATION AND OVER-EXPRESSION OF THE EGFR AND ERBB-2 GENES IN HUMAN ESOPHAGEAL ADENOCARCINOMAS [J].
ALKASSPOOLES, M ;
MOORE, JH ;
ORRINGER, MB ;
BEER, DG .
INTERNATIONAL JOURNAL OF CANCER, 1993, 54 (02) :213-219
[4]
Tumor marker expression is predictive of survival in patients with esophageal cancer [J].
Aloia, TA ;
Harpole, DH ;
Reed, CE ;
Allegra, C ;
Moore, MBH ;
Herndon, JE ;
D'Amico, TA .
ANNALS OF THORACIC SURGERY, 2001, 72 (03) :859-866
[5]
Prospective study of cyclin D1 overexpression in Barrett's esophagus: Association with increased risk of adenocarcinoma [J].
Bani-Hani, K ;
Martin, IG ;
Hardie, LJ ;
Mapstone, N ;
Briggs, JA ;
Forman, D ;
Wild, CP .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2000, 92 (16) :1316-1321
[6]
Cost-Effectiveness of Endoscopic Screening Followed by Surveillance for Barrett's Esophagus: A Review [J].
Barbiere, Josephine M. ;
Lyratzopoulos, Georgios .
GASTROENTEROLOGY, 2009, 137 (06) :1869-1876
[7]
Böttger TG, 1998, CANCER-AM CANCER SOC, V83, P1074, DOI 10.1002/(SICI)1097-0142(19980915)83:6<1074::AID-CNCR4>3.0.CO
[8]
2-8
[9]
Does screening for Barrett's esophagus and adenocarcinorna of the esophagus prolong survival? [J].
Dellon, ES ;
Shaheen, NJ .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (20) :4478-4482
[10]
A phase II study of gefitinib monotherapy in advanced Esophageal adenocarcinoma: Evidence of gene expression, cellular, and clinical response [J].
Ferry, David R. ;
Anderson, Mark ;
Beddard, Kate ;
Tomlinson, Simon ;
Atherfold, Paul ;
Obszynska, Jolanta ;
Harrison, Rebecca ;
Jankowski, Janusz .
CLINICAL CANCER RESEARCH, 2007, 13 (19) :5869-5875