The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

Abstract

Abstract. The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, welldifferentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to tumor site, particularly regarding anti-EGFR targeted treatment. IntroductionColorectal cancer (CRC) is one of the most common malignancies and remains a major cause of cancer mortality in the West (1). It is also a multi-pathway disease with disparate subgroups exhibiting distinct genetic and clinicopathological features, and probably different outcomes (2). This may be the main reason for the variability in treatment response observed among patients of the same disease stage. Therefore, a combination of the conventional TNM staging classification (at present, the major prognostic indicator) with certain molecular markers involved in CRC tumorigenesis, with verified prognostic and predictive impact, is one of the main objectives of research worldwide (3).Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein member of the tyrosine-kinase receptor family, encoded by the c-erB1 proto-oncogene and is considered as a major regulator of several distinct cellular pathways. Activation of EGFR promotes carcinogenesis, by increasing prol...

Are ADC values of readout-segmented echo-planar diffusion-weighted imaging (RESOLVE) correlated with pathological prognostic factors in rectal adenocarcinoma?

“…Some studies [ 24 ] have revealed that EGFR-positive rectal cancer cells are more proliferative and infiltrative, which correlate with the TNM stage and LB metastasis, indicating that the high expression of EGFR is associated with the high invasiveness and metastasis of tumours. According to the statistical data reported in the current literature, there are relatively large differences in the expression rates of EGFR in RAC, reporting that the over-expression of EGFR was observed in 65–97% patients with RAC [ 25 , 26 ]. In the present study, we found an 80% positive expression rate of EGFR in the patients with RAC.…”

Comparison of 627 patients with right‐ and left‐sided colon cancer in China: Differences in clinicopathology, recurrence, and survival

“…Studies have also suggested that the disease biology is different between right- and left-sided colon cancers. 24 , 25 , 26 , 27 Microsatellite instability is more common in right-sided cancers, whereas chromosomal instability is more characteristic of left-sided cancers. 28 Many studies have found that patients with microsatellite instability tumors have a better prognosis and that DNA MMR status is an independent favorable predictor of survival.…”

“…Prior studies have demonstrated significant gene expression differences between right and left colon cancers. 25 , 26 , 34 , 35 Glebov et al 25 found that more than 1000 genes were expressed differentially in adult ascending versus descending colon, with 165 genes showing >2-fold and 49 genes showing >3-fold difference in expression levels. Papagiorgis et al 26 reported that the pattern of EGFR expression varies with disease progression and aggressiveness in CRC depends on tumor location.…”

“…25 , 26 , 34 , 35 Glebov et al 25 found that more than 1000 genes were expressed differentially in adult ascending versus descending colon, with 165 genes showing >2-fold and 49 genes showing >3-fold difference in expression levels. Papagiorgis et al 26 reported that the pattern of EGFR expression varies with disease progression and aggressiveness in CRC depends on tumor location. BRAF mutations are observed more frequently in right-sided colon cancer 35 and the BRAF V600E mutation is an independent unfavorable prognostic factor for survival in stage II–III colon cancer patients.…”

Lack of RING Finger Domain (RFD) Mutations of the c-Cbl Gene in Oral Squamous Cell Carcinomas in Chennai, India

“…1 , Rajendran Shanmugam Muthupalani 2,3 , Arvind Ramanathan 3 * phospho-tyrosine residues on the EGFR (pY1148, pY1086, pY1101) enable differential activation of a number of other proteins in response to EGF stimulation (Papagiorgis et al, 2012). ERK2 is the founding member of MAPK family, the activation of which is mediated via Ras/Raf/MEK kinase pathway (Arvind et al, 2005;Mahalingam et al, 2008).…”