Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

John, Thomas; Liu, Geoffrey; Tsao, Ming‐Sound

doi:10.1038/onc.2009.197

Cited by 176 publications

(134 citation statements)

References 110 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…Mutations in the tyrosine kinase domain of EGFR have been traditionally detected using direct DNA sequencing 40 or other methods. 24,41,42 Use of antibodies that are specific to mutated protein present a potentially less expensive and more routine method for mutation detection.…”

Section: Discussionmentioning

confidence: 99%

Standardization of Epidermal Growth Factor Receptor (EGFR) Measurement by Quantitative Immunofluorescence and Impact on Antibody-Based Mutation Detection in Non–Small Cell Lung Cancer

Dimou

Agarwal

Anagnostou

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Challenges in measurement of epidermal growth factor receptor (EGFR) protein expression have led to conflicting data on its prognostic value and discontinuation of its use for prediction of response. Herein is described a quantitative standardized assay for EGFR and its use in a series of retrospective cohorts of patients with nonsmall cell lung cancer (NSCLC). The AQUA technology of quantitative immunofluorescence was used in conjunction with Western blot analysis to calculate the absolute concentration of EGFR in two independent NSCLC cohorts (170 from Yale New Haven Hospital and 335 from Sotiria and Patras Hospitals in Greece). EGFR and mutated EGFR were measured using D38B1 antibody and two mutation-specific antibodies. All patients positive or borderline for mutation-specific antibody were genotyped. A threshold for reproducible detection of EGFR was defined as 0.85 ng/ g total protein. EGFR expression demonstrated no prognostic value in either cohort. The mutation rate was 1.79% in the Yale cohort, and 1.52% in the Sotiria/Patras cohort, with no antibody detection-based false-positive cases. No mutations were detected for EGFR concentrations <1.46 ng/ g total protein. In summary, accurate measurement of EGFR still shows no prognostic value in NSCLC. In these two population-based cohorts, the antibody-based EGFR mutation rate was lower than has been frequently reported.

show abstract

Section: Discussionmentioning

confidence: 99%

Standardization of Epidermal Growth Factor Receptor (EGFR) Measurement by Quantitative Immunofluorescence and Impact on Antibody-Based Mutation Detection in Non–Small Cell Lung Cancer

Dimou

Agarwal

Anagnostou

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…To date, the secondary resistance mutations contain Thr790Met (T790M), Asp761Tyr (D761Y) (11), Ser 768 Ile (S768I) (12), Leu747Ser (L747S) (13) and Thr854Ala (T854A) (14). The T790M mutation is found in approximately 50% of all patients with acquired resistance to TKI (15), while other resistance mutations are relatively rare. Compared to the activating mutations, the resistance mutations are expected to have conformational changes to reduce both gene activation and TKI sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy

et al. 2012

View full text Add to dashboard Cite

Abstract. The development and clinical application of TK domain inhibitors (TKIs) provide important insights into the broader field of cancer-targeted therapies. To discuss the recent advances in the atomic level understanding of EGFR TK domain mutations, we aim at highlighting the current and future importance of these studies on malignancies where the TK domain is improperly activated. The analysis is conducted on published TK domain crystal structures deposited in the Protein Data Bank, or homology structures generated by homology modeling and AutoDock 4.2 software using the program O. Mutations in exon 19 are the most common pathogenic mutations, so the crystal structures with these mutations are analyzed and compared in detail. In addition, we demonstrate how these crystal structures of EGFR conformation with TK domain mutations and those binding with small molecule inhibitors unveil the active or inactive mechanisms. As to the increasing resistance to the TKI, we summarize the progress on overcoming this challenge. Simultaneously, we predict the structure of BIKW-2992 binding to EGFR and compare it with the validated structure of HKI-272. It is hoped that a more accurate resistance mechanism would be found. In brief, we believe that this research will provide insights into EGFR targeted therapies.

show abstract

“…Chromosomal aberrations in tumors lead to DNA copy number alterations, with an associated gain or loss of genes crucial for tumor progression (14)(15)(16)(17)(18). The majority of the aCGH experiments have focused on the genome-wide screening of CNVs, and the data obtained are generally informative, but not definitive.…”

Section: Introductionmentioning

confidence: 99%

Coexistence of copy number increases of ZNF217 and CYP24A1 in colorectal cancers in a Chinese population

Fang

Xiong²,

Zhang³

et al. 2010

Oncology Letters

View full text Add to dashboard Cite

Abstract. Evidence suggests that the amplification of chromosome 20q13 is common in colorectal cancers (CRCs). Certain candidate oncogenes located in this region are reported to be associated with tumorigenesis of the gastrointestinal tract. The functional impact of such regions should be extensively investigated in a large number of clinical samples. In this study, 145 CRC samples with matched adjacent normal tissues were collected from a Chinese population for copy number variation (CNV) analysis. Our results showed that both the copy numbers of 25-hydroxy vitamin D3 24-hydroxylase (CYP24A1) and zinc-finger protein 217 (ZNF217) were amplified in a relatively high percentage of CRC samples (51.1 and 60%, respectively). The mRNA expression levels of both CYP24A1 and ZNF217 were found to have increased in the collected CRC samples as compared to the matched adjacent normal tissues. ZNF217, but not CYP24A1, showed a positive correlation between copy number increases and mRNA overexpression. These findings suggest the potential role of CNVs of certain oncogenes in CRCs.

show abstract

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

Cited by 176 publications

References 110 publications

Standardization of Epidermal Growth Factor Receptor (EGFR) Measurement by Quantitative Immunofluorescence and Impact on Antibody-Based Mutation Detection in Non–Small Cell Lung Cancer

Standardization of Epidermal Growth Factor Receptor (EGFR) Measurement by Quantitative Immunofluorescence and Impact on Antibody-Based Mutation Detection in Non–Small Cell Lung Cancer

Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy

Coexistence of copy number increases of ZNF217 and CYP24A1 in colorectal cancers in a Chinese population

Contact Info

Product

Resources

About