Dataset Information

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.

SUBMITTER: Morris LG

PROVIDER: S-EPMC3223475 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Morris Luc G T LG Taylor Barry S BS Bivona Trever G TG Gong Yongxing Y Eng Stephanie S Brennan Cameron W CW Kaufman Andrew A Kastenhuber Edward R ER Banuchi Victoria E VE Singh Bhuvanesh B Heguy Adriana A Viale Agnes A Mellinghoff Ingo K IK Huse Jason J Ganly Ian I Chan Timothy A TA

Proceedings of the National Academy of Sciences of the United States of America 20111107 47

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 ...[more]

PMID: 22065749

Similar Datasets

Project description:BackgroundLymph node count (LNC) from neck dissection has been associated with undernutrition and survival in head and neck squamous cell carcinoma (HNSCC). As local components of the immune system, cervical lymph nodes may reflect anti-tumor immune status. This study investigates the relationship between decreased LNC, formation of tertiary lymphoid structures (TLS), and primary tumor infiltration by lymphocytes in undernourished patients.MethodsA matched-cohort study was conducted in a tertiary medical center, where neck dissection quality was standardized for a total of 384 subjects that were evaluated. Six head and neck cancer patients that underwent primary surgery including neck dissection with low LNC and BMI (low BMI < 23, low LNC ≤ 5.6 per neck level) were matched by stage, p16 status, and subsite to 16 patients with normal BMI and high LNC. Multiplexed immunohistochemistry was used to evaluate the tumor-infiltrating lymphocytes and the number and quality of TLS within primary tumors. Whole primary cancers underwent automated analysis and counting of leukocytes after multiplexed immunohistochemistry staining of tumor slides. A head and neck pathologist blindly scored the number and maturity of TLS. Descriptive statistics were used to analyze outcomes.ResultsThe patients with low BMI and low LNC had significantly fewer CD3 (p = 0.0136), CD8 (p = 0.0003), and CD20 (p = 0.0334) cells in their primary tumors compared to patients with normal BMI and LNC. The low BMI low LNC patients also had fewer mature TLS (0.83/tumor) in their primary cancers compared to patients with normal BMI and high LNC (5.4/tumor) and also had greater than fourfold lower mature TLS density (TLS per μm2 mean) (6.34 × 10-9 vs. 2.82 × 10-8), with significantly worsened survival relative to patients with low BMI and normal LNC and patients with normal BMI.ConclusionLow LNC predicts worsened survival only in low BMI HNSCC patients with non-HPV related tumors and in these patients is associated with markers of immunosuppression such as fewer tumor-infiltrating CD8+ T-cells, CD20+ cells, and fewer TLS in primary cancers compared to matched normal BMI patients with high LNC.

Dataset Information

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Publications

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets