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.
authors: Human Oncology and Pathogenesis Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Luc G T
authors: LG
authors: Morris
authors: Barry S
authors: BS
authors: Taylor
authors: Trever G
authors: TG
authors: Bivona
authors: Yongxing
authors: Y
authors: Gong
authors: Stephanie
authors: S
authors: Eng
authors: Cameron W
authors: CW
authors: Brennan
authors: Andrew
authors: A
authors: Kaufman
authors: Edward R
authors: ER
authors: Kastenhuber
authors: Victoria E
authors: VE
authors: Banuchi
authors: Bhuvanesh
authors: B
authors: Singh
authors: Adriana
authors: A
authors: Heguy
authors: Agnes
authors: A
authors: Viale
authors: Ingo K
authors: IK
authors: Mellinghoff
authors: Jason
authors: J
authors: Huse
authors: Ian
authors: I
authors: Ganly
authors: Timothy A
authors: TA
authors: Chan
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D002869:Chromosome Aberrations; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D019295:Computational Biology; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000201:enzymology*; D006801:Humans; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; C516883:PTPRS protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2