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Challenges in EGFRvIII detection in head and neck squamous cell carcinoma

Wheeler, SE and Egloff, AM and Wang, L and James, CD and Hammerman, PS and Grandis, JR (2015) Challenges in EGFRvIII detection in head and neck squamous cell carcinoma. PLoS ONE, 10 (2).

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Abstract

© 2015 Wheeler et al. Objective Head and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2-7 and has been reported to be present in up to 20-40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC. Materials and Methods Fixed HNSCC and glioma tissues were analyzed by fluorescence in situ hybridization for EGFR amplification. DNA and RNA from fresh frozen specimens were used to determine the presence of EGFRvIII transcripts and the mechanisms of expression via PCR, RT-PCR and RNA sequencing. Results Unlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2-7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings. Conclusion These findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altered form of EGFR in HNSCC tumors.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wheeler, SEsam125@pitt.eduSAM125
Egloff, AM
Wang, L
James, CD
Hammerman, PS
Grandis, JRjgrandis@pitt.eduJGRANDIS
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorTeh, Muy-TeckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 6 February 2015
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0117781
Schools and Programs: School of Medicine > Pathology
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Other ID: NLM PMC4320077
PubMed Central ID: PMC4320077
PubMed ID: 25658924
Date Deposited: 12 May 2015 18:22
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/24086

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