5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

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Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

Oncology Letters ◽

10.3892/ol.2017.5936 ◽

2017 ◽

Vol 13 (5) ◽

pp. 3958-3966 ◽

Cited By ~ 9

Author(s):

Naoto Yamamoto ◽

Takashi Oshima ◽

Kazue Yoshihara ◽

Toru Aoyama ◽

Tsutomu Hayashi ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Expression Levels ◽

Clinicopathological Significance ◽

Gene Expression Levels ◽

Igfbp 3

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Molecular determinants of capecitabine efficacy in colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3606 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3606-3606

Author(s):

D. Vallbohmer ◽

H. Kuramochi ◽

D. Shimizu ◽

K. D. Danenberg ◽

J. N. Nielsen ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Clinical Outcome ◽

Single Agent ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Expression Levels ◽

Cox 2 ◽

Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

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Heparanase and Survivin—potential markers of aggressiveness of colon cancers

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14524 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14524-14524

Author(s):

A. C. Hoffmann ◽

C. Hoffmann ◽

K. D. Danenberg ◽

H. J. Lenz ◽

P. V. Danenberg

Keyword(s):

Gene Expression ◽

Liver Metastasis ◽

Decision Tree ◽

Cancer Metastasis ◽

Decision Tree Analysis ◽

Tissue Samples ◽

Tree Analysis ◽

Expression Levels ◽

Colon Cancers ◽

Gene Expression Levels

14524 Background: Survivin is an inhibitor of apoptosis and specifically expressed in several human cancers. Heparanase seems to play an important role in cancer metastasis, angiogenesis and regulation of COX-2 expression. The purpose of this pilot study was to evaluate whether there is a difference in the level of survivin and heparanase expression in paraffin-embedded tissue from patients with colon cancer with and without metastasis. Methods: Paraffin-embedded tissue samples were obtained from 32 patients with primary colon tumors with (n = 15) and without liver metastases (n = 17) at the time of diagnosis. After laser capture microdissection direct quantitative real-time reverse transcriptase PCR (RT-PCR, TaqMan™) assays were performed in triplicates to determine survivin and heparanase gene expression levels. Gene expression was normalized with beta-Actin. Decision tree analysis was used to assess whether higher levels of these genes are associated with the existence of metastasis. Results: Neither survivin nor heparanase gene expression alone showed a significant relationship with the pM-Stage, although the detection levels of heparanase showed a tendency towards significant correlation with the existence of liver metastasis (p = 0.06). Decision tree analysis was used to split patients into two groups based on cut-off values of gene expression most closely associated with the pM-stage. The groupings determined by this analysis were significantly differently correlated with metastasis by Spearman’s test (p=0.03). Conclusions: Our results show that high expression levels of both survivin and heparanase in paraffin- embedded tissue are significantly correlated with the pM-Stage in this patient cohort. In conclusion, using intratumoral survivin and heparanase gene expression levels might be useful to identify patients at risk for liver metastasis. Prospective and larger clinical studies are warranted to validate our preliminary findings. No significant financial relationships to disclose.

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Overexpression of EphA4 gene and reduced expression of EphB2 gene: Correlation with liver metastasis in colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15129 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15129-e15129

Author(s):

T. Oshima ◽

N. Yamamoto ◽

T. Sato ◽

Y. Nagano ◽

S. Fujii ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Liver Metastasis ◽

Tyrosine Kinases ◽

Large Family ◽

Cancer Tissue ◽

Eph Receptors ◽

Expression Levels ◽

Relative Expression ◽

Over Expression

e15129 The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biologic functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relations of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relations between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that over-expression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Over-expression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer. No significant financial relationships to disclose.

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