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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers
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Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

机译：表皮生长因子受体（EGFR）/ PI3K通路的基因组解剖揭示了头颈部癌中EGFR磷酸酶PTPRS的频繁缺失

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摘要

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.
机译：PI3K和表皮生长因子受体（EGFR）途径的激活能够驱动多种人类癌症的发生，包括头颈部鳞状细胞癌。目前，头颈部鳞状细胞癌患者使用靶向药物，例如西妥昔单抗和厄洛替尼，但在这种疾病中，导致途径激活并确定对药理抑制反应的基因组改变仍然不清楚。在这里，我们介绍了EGFR / PI3K途径的详细解剖，包括核心途径组分的测序和高分辨率基因组拷贝数评估。在PIK3CA中发现了突变（6％），但在其他途径基因（如PTEN和EGFR）中未观察到点突变。相反，我们观察到该途径中基因的频繁拷贝数变化，包括PIK3CA，EGFR。蛋白酪氨酸磷酸酶受体S（PTPRS）。和RICTOR。总体而言，在74％的头颈部肿瘤中发现了激活的遗传途径改变。重要的是，EGFR磷酸酶PTPRS的基因内微缺失很常见（26％），从而将该基因鉴定为19p13缺失的靶标。 PTPRS的缺失促进了EGFR / PI3K途径的激活，调节了对EGFR抑制的抵抗力，并强烈确定了具有激活EGFR突变的肺癌患者的生存率。这些发现对于我们对头颈癌肿瘤发生的理解以及针对这种恶性肿瘤的靶向药物的使用具有重要意义。

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    Luc G. T. Morris; Barry S. Taylor; Trever G. Bivona; Yongxing Gong; Stephanie Eng; Cameron W. Brennan; Andrew Kaufman; Edward R. Kastenhuber; Victoria E. Banuchi; Bhuvanesh Singh; Adriana Heguy; Agnes Viale; Ingo K. Mellinghoff; Jason Huse; Ian Ganly; Timothy A. Chan;

  • 作者单位

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Departments of Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Departments of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Departments of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Departments of Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Departments of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Human Oncology and Pathogenesis Program, Departments of Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Departments of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    oral cancer; tumor suppressor;

    机译：口腔癌;抑癌剂;

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