Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers Journal Article
| Authors: | Morris, L. G. T.; Taylor, B. S.; Bivona, T. G.; Gong, Y.; Eng, S.; Brennan, C. W.; Kaufman, A.; Kastenhuber, E. R.; Banuchi, V. E.; Singh, B.; Heguy, A.; Viale, A.; Mellinghoff, I. K.; Huse, J.; Ganly, I.; Chan, T. A. |
| Article Title: | Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers |
| Abstract: | Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR. In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA, EGFR, protein tyrosine phosphatase receptor S (PTPRS), and RICTOR. In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy. |
| Keywords: | signal transduction; cancer survival; controlled study; human tissue; unclassified drug; gene mutation; gene sequence; gene deletion; mutation; squamous cell carcinoma; carcinoma, squamous cell; polymerase chain reaction; gene targeting; computational biology; epidermal growth factor receptor; lung cancer; rna interference; receptor, epidermal growth factor; enzyme activation; phosphatidylinositol 3 kinase; blotting, western; head and neck neoplasms; chromosomes, human, pair 19; tumor suppressor; protein tyrosine phosphatase; receptor-like protein tyrosine phosphatases, class 2; mutation rate; chromosome aberrations; gene dosage; comparative genomic hybridization; gene knockdown techniques; head and neck carcinoma; sequence analysis, dna; oral cancer; dna copy number variations; head and neck squamous cell carcinoma; chromosome 19p; phosphatidylinositol 3-kinases; protein tyrosine phosphatase receptor s |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 108 |
| Issue: | 47 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2011-11-22 |
| Start Page: | 19024 |
| End Page: | 19029 |
| Language: | English |
| DOI: | 10.1073/pnas.1111963108 |
| PROVIDER: | scopus |
| PMCID: | PMC3223475 |
| PUBMED: | 22065749 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 January 2012" - "CODEN: PNASA" - "Source: Scopus" |
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