Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients

Scartozzi, Mario; Bearzi, Italo; Mandolesi, Alessandra; Giampieri, Riccardo; Faloppi, Luca; Galizia, Eva; Loupakis, Fotios; Zaniboni, Alberto; Zorzi, Fausto; Biscotti, Tommasina; Labianca, Roberto; Falcone, Alfredo; Cascinu, Stefano

doi:10.1038/bjc.2011.161

Cited by 66 publications

(48 citation statements)

References 26 publications

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“…Interestingly, tumors that harbor these mutations still respond to panitumumab as this binds to a distinct epitope of the molecule. Furthermore, silencing of EGFR by EGFR gene methylation has been reported to underlie the failure of anti-EGFR antibody therapy (3).…”

Section: Colorectal Cancer Heterogeneity and Predictors Of Responsementioning

confidence: 99%

“…The role of mutations in KRAS as a selection marker for anti-EGFR therapy has been extensively validated, but it is estimated that only 35% of KRAS wild-type tumors do respond to anti-EGFR therapy (1). The list of additional genetic and epigenetic characteristics that are associated with anti-EGFR therapy resistance, albeit sometimes only in preclinical models, is rapidly expanding and includes, among others, mutations in BRAF and PIK3CA, epigenetic silencing of EGFR expression, augmented expression of other receptor tyrosine kinases (RTK), including MET, and high expression of the MET ligand hepatocyte growth factor (HGF) in the tumor microenvironment (2,3). Until it will be feasible to routinely obtain comprehensive molecular profiles of individual tumors, it will be challenging to determine the presence of all these modifiers of therapy efficacy in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

et al. 2015

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Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in patients. For EGFRtargeted therapy, many mechanisms of resistance have been uncovered, for example, mutations in KRAS and BRAF, and upregulation of alternative receptors. Currently, routine testing for all known modifiers of response is unpractical, and as a result, decision-making for anti-EGFR therapy is still largely based on assessing the mutation status of an individual gene (KRAS). Recently, comprehensive classifications of colorectal cancer have been presented that integrate many of the (epi-)genetic and microenvironmental factors that contribute to colorectal cancer heterogeneity. These classification systems are not only of prognostic value but also predict therapy efficacy, including the response to anti-EGFR agents. Therefore, molecular subtypebased stratification to guide therapeutic decisions is a promising new strategy that might overcome the shortcomings of single gene testing in colorectal cancer as well as in other malignancies. Furthermore, the development of new agents in a disease subtype-specific fashion has the potential to transform drug-discovery studies and generate novel, more effective therapies. Cancer Res; 75(2); 245-9. Ó2014 AACR.

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Section: Colorectal Cancer Heterogeneity and Predictors Of Responsementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

et al. 2015

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“…This implied that EGFR expression in cancerous tissue might be regulated by methylation, although elucidation of the specific regulatory mechanism would still need further research. In addition, it has been shown that the median progression-free survival time in patients with or without methylation was 2.4 and 7.4 months, respectively, whereas the overall survival times were 6.1 and 17.8 months, respectively (Scartozzi et al, 2011). With the increase of malignancy staging, the methylation level in patients also rises.…”

Section: Discussionmentioning

confidence: 89%

Relationship of EGFR DNA methylation with the severity of non-small cell lung cancer

Li¹,

Jing²,

Liu³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to study the relationship of EGFR DNA methylation with the severity of non-small-cell lung cancer (NSCLC). We enrolled 54 patients with NSCLC between March 2013 and June 2014 from Department of Cardiothoracic Surgery in our hospital. The methylation levels in the promoter region of the EGFR gene in cancerous and pericarcinomatous tissue were tested by pyrosequencing. EGFR mRNA expression levels were detected by real-time reversetranscription polymerase chain reaction. The SPSS software was used for data analysis. We found that EGFR gene methylation levels showed no significant differences among patients of different gender, age, or smoking status. EGFR DNA methylation levels significantly increased (P < 0.05) following NSCLC malignancy upgrading, and showed negative correlation with mRNA expression (P = 0.041). DNA methylation levels of cancerous tissues were significantly higher compared to the corresponding pericarcinomatous tissues (P < 0.05) at stages I, II, and IIIA. The methylation levels at loci 3, 6, 9 among the detected CpG islands were higher in the cancer tissues at each stage (P < 0.05). In summary, our 11915-11923 (2015) results suggest that the DNA methylation levels of EGFR can be used as an important indicator for the stage of cancer tissue malignancy.

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“…Similar to protein coding genes, miRs are downregulated through epigenetic mechanisms (11,22,23). Although methylation typically affects TSGs, it also occurs in oncogenes, such as COX219, telomerase reverse transcriptase and epidermal growth factor receptor, silencing their expression (24)(25)(26)(27). miR-9 is reportedly involved in an oncogenic as well as a tumor-suppressing manner in human malignancies.…”

Section: Mir-9s Methylation and Clinicopathological Factorsmentioning

confidence: 99%

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers

Muraoka

Soh

Toyooka

et al. 2012

Molecular and Clinical Oncology

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Abstract. MicroRNAs (miRs) contribute to cancer development and progression by acting as oncogenes and tumor suppressor genes. miR-9 family members (miR-9s), including miR-9-1, 9-2 and 9-3, have been shown to be oncogenically involved through the downregulation of E-cadherin expression, which promotes the epithelial-mesenchymal transition. Tumor suppressive roles of miR-9s have also been reported to silence miR-9 through methylation, which is associated with an shortened overall survival (OS) period in several types of cancer. In this study, the impact of miR-9s methylation on non-small cell lung cancers (NSCLC) was investigated. In total, 293 resected NSCLC samples were examined and the miR-9s methylation status was determined using a combined bisulfite restriction analysis. miR-9 expression was analyzed by in situ hybridization. Methylation of miR-9-1, 9-2 and 9-3 was present in 20 (7%), 33 (11%) and 34 (12%) of the cases, respectively. Methylation of any miR-9s (miR-9s methylation) was observed in 76 of the cases (26%), and miR-9 expression was silenced in cases with miR-9s methylation. Logistic regression analysis demonstrated that male gender [odds ratio (OR), 2.0; 95% confidence interval (95% CI), 1.1-3.6; P=0.01] and pathologically negative lymph node metastasis (OR, 4.8; 95% CI, 1.4-17.2; P=0.002) were independent relative factors for miR-9s methylation. Additionally, miR-9s methylation [hazard ratio (HR), 4.2; 95% CI, 1.2-27.0; P=0.026] and early pathological stage (HR, 8.3; 95% CI, 2.1-28.6; P=0.004) were found to be independent predictive factors for prolonged OS time by the Cox proportional hazard test. miR-9s methylation which induces expression silencing is common in NSCLC cases without lymph nodal metastasis, suggesting that miR-9s are oncogenically involved in NSCLC carcinogenesis through the promotion of tumor metastasis.

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Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients

Cited by 66 publications

References 26 publications

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

Relationship of EGFR DNA methylation with the severity of non-small cell lung cancer

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers

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