Lung squamous cell carcinoma subtypes: genomic abberations and clinical detection

描述(申请人提供)：肺癌是美国男性和女性癌症相关死亡的最大原因。最近对特定类型肺癌的认识导致了更有效的、量身定制的治疗方法。其中一种主要类型是肺鳞状细胞癌(LSCC)，它是一种异质性疾病，临床结果多种多样。最近的几项研究使用基因表达微阵列确定了LSCC亚型，但还没有尝试验证这些结果，这是LSCC亚型用于临床决策或未来研究的先决条件。导致肿瘤基因表达发生巨大变化的主要原因之一是基因组拷贝数或染色体片段的得失。我们的核心假设是喉癌具有可复制的分子亚型，这些亚型由基因表达和拷贝数的变化定义，代表着不同的临床疾病和生物学过程。在前期工作中，我们的实验室分析了来自多个独立队列的已发表的原始微阵列数据，并证明了四种LSCC亚型可以可靠地识别。为了实现我们的核心假设，我们组建了一个新的独立LSCC队列(UNC)。我们假设这四个先验的LSCC亚型是强健的生物学疾病，因此将存在于独立的UNC队列中。UNC队列将通过基因表达微阵列进行分析。UNC队列亚型将由历史队列预测，并通过UNC内部预测进行验证。我们通过细胞带差异基因表达推断拷贝数差异的初步分析显示了几个亚型特异区：3q22-29、8q24和18q12。我们假设这些区域和其他区域将区分LSCC亚型。为了验证这一假设，我们将通过计算检测由SNP微阵列测量的UNC队列基因组拷贝数。为了将我们的结果转化为临床应用，我们将开发一种免疫组织化学分析方法，可以预测临床组织标本的LSCC亚型。然后，我们将使用我们的方法在一个大型的独立队列中预测LSCC亚型，并评估LSCC亚型是否有不同的临床过程，如生存、转移模式和对化疗的反应。公共卫生相关性：一种新的分子LSCC分类可能有助于解释这种疾病的各种临床结果，并为新的专门治疗提供基础。通过这一建议开发的检测方法将允许在临床标本中识别LSCC亚型，并朝着常规临床诊断迈出了一步。亚型特异性基因组拷贝数异常可能与喉癌的病因学模型有关。

DESCRIPTION (provided by applicant): Lung cancer is the greatest cause of cancer-related deaths of men and women in the United States. Recent appreciation of the specific types of lung cancer has led to more effective, tailored therapies. One of the major types is lung squamous cell carcinoma (LSCC), which is a heterogeneous disease with a wide range of clinical outcomes. Several recent studies identified LSCC subtypes using gene expression microarrays, but there has been no attempt to validate these results, which is a prerequisite if LSCC subtypes are to be used in clinical decisions or future research. One of the principal drivers of the wildly altered tumor gene expression is genomic copy number or the gain and loss of chromosomal segments. Our core hypothesis is LSCC has reproducible molecular subtypes defined by alterations in gene expression and copy number, which represent distinct clinical diseases and biological processes. In preliminary work, our laboratory analyzed published raw microarray data from multiple independent cohorts and demonstrated that four LSCC subtypes can be reliably recognized. To pursue our core hypothesis, we have assembled a new independent LSCC cohort (UNC). We hypothesize the four a priori LSCC subtypes are robust biological diseases and as such will exist in the independent UNC cohort. The UNC cohort will be assayed by gene expression microarrays. UNC cohort subtype will be predicted by historical cohorts and validated with internal UNC predictions. Our preliminary analysis of inferring copy number differences by cytoband differential gene expression demonstrated several subtype-specific regions: 3q22-29, 8q24, and 18q12. We hypothesize that these and additional regions will differentiate the LSCC subtypes. To test this hypothesis, we will computationally detect UNC cohort genomic copy number, measured by SNP microarrays. To translate our results into a clinical application, we will develop an immunohistochemical assay that can predict LSCC subtype of clinical tissue specimens. We will then use our assay to predict LSCC subtype in a large independent cohort and evaluate whether LSCC subtypes have distinct clinical courses, such as survival, metastasis patterns, and response to chemotherapy. PUBLIC HEALTH RELEVANCE: A new molecular LSCC classification may help explain the wide variety of clinical outcomes in this disease and provide a basis for new specialized therapies. The assay developed through this proposal will allow LSCC subtype identification in clinical specimens and is a step towards a routine clinical diagnostic. Subtype-specific genomic copy number aberrations may contribute to etiological models of LSCC.