Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Bormann, Felix; Stinzing, Sebastian; Tierling, Sascha; Morkel, Markus; Markelova, Maria Rivera; Walter, Jörn; Weichert, Wilko; Roßner, Florian; Kuhn, Natalia; Perner, Juliane; Dietz, Johanna; Ispasanie, Sylvia; Dietel, Manfred; Schäfer, Reinhold; Heinemann, Volker; Sers, Christine

doi:10.1002/ijc.31892

Cited by 23 publications

(17 citation statements)

References 35 publications

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“…Emerging evidences raise the possibility of alternative, non-genetic mechanisms contributing to the appearance of cells that can evade EGFR drug treatment [72,73,74,75,76].…”

Section: Alternative Non-genetic Mechanisms That Evade Egfr-targetmentioning

confidence: 99%

“…Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Recently, an intragenic methylation of AREG and EREG genes has been shown to be inversely correlated with their expression in both colorectal cancer cells and human colorectal cancer samples [75]. Retrospective comparison of colorectal cancer patients treated with anti-EGFR revealed that AREG expression is better than AREG gene methylation to predict clinical follow-up [68].…”

Section: Alternative Non-genetic Mechanisms That Evade Egfr-targetmentioning

confidence: 99%

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Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

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“…Emerging evidences raise the possibility of alternative, non-genetic mechanisms contributing to the appearance of cells that can evade EGFR drug treatment [72,73,74,75,76].…”

Section: Alternative Non-genetic Mechanisms That Evade Egfr-targetmentioning

confidence: 99%

Section: Alternative Non-genetic Mechanisms That Evade Egfr-targetmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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“…BioMed Research International derived stem cells [41]. In colorectal cancer, EREG serves as a biomarker of anti-EGFR therapy [42]. The inhibition of EGFR signaling in pancreatic cancer may lead to a decrease in the growth and invasion of pancreatic tumors [43].…”

mentioning

confidence: 99%

Identification of Prognostic Immune-Related Genes in Pancreatic Adenocarcinoma and Establishment of a Prognostic Nomogram: A Bioinformatic Study

Deng

Jin

et al. 2020

BioMed Research International

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Background. The prognosis of pancreatic adenocarcinoma (PAAD) is extremely poor and has not been improved. Thus, an effective method to assess the prognosis of patients must be established to improve their survival rate. Method. This study investigated immune-related genes that could be used as potential therapeutic targets for PAAD. Level 3 gene expression data from the PAAD cohort and the relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. For validation, other PAAD datasets (DSE62452) were downloaded from the Gene Expression Omnibus (GEO) database. The PAAD datasets from TCGA and GEO were used to screen immune-related genes through the Molecular Signatures Database using gene set enrichment analysis. Then, the overlapping immune-related genes of the two datasets were identified. Coexpression networks of the immune-related genes were constructed. Results. A signature of three immune-related genes (CKLF, ERAP2, and EREG) was identified in patients with PAAD. The signature could be used to divide the patients with PAAD into high- and low-risk groups based on their median risk score. Multivariate Cox regression analysis was performed to determine the independent prognostic factors of PAAD. Time-dependent receiver operating characteristic (ROC) curve analysis was conducted to assess the prediction accuracy of the prognostic signature. Last, a nomogram was established to assess the individualized prognosis prediction model based on the clinical characteristics and risk score of the TCGA PAAD dataset. The accuracy of the prognostic signature was further evaluated through functional evaluation and principal component analysis. Conclusions. The results indicated that the signature of three immune-related genes had excellent predictive value for PAAD. These findings might help improve personalized treatment and medical decisions.

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“…However, using MLH1 promoter methylation as a surrogate for CpG island methylator phenotype status, one study found that approximately 25% of CIMP-negative samples exhibited high levels of methylation and low levels of EREG expression [22]. Furthermore, AREG and EREG mRNA expression correlated with gene body methylation but not with promoter methylation in CRC cell lines, as observed in the study by Bormann et al [21]. These results suggest that the mechanism of epigenetic regulation of EREG might be more complex.…”

Section: Discussionmentioning

confidence: 98%

High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy

et al. 2020

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Background/Aim: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. Methods: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). Results: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). Conclusion: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.

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Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer

Cited by 23 publications

References 35 publications

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Identification of Prognostic Immune-Related Genes in Pancreatic Adenocarcinoma and Establishment of a Prognostic Nomogram: A Bioinformatic Study

High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy

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