Lung squamous cell carcinoma subtypes: genomic abberations and clinical detection

描述（由申请人提供）：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已经导致了更有效、更有针对性的治疗方法。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，具有广泛的临床结果。最近的几项研究使用基因表达微阵列确定了LSCC亚型，但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。肿瘤基因表达剧烈改变的主要驱动因素之一是基因组拷贝数或染色体片段的增加和减少。我们的核心假设是LSCC具有可重复的分子亚型，由基因表达和拷贝数的改变定义，代表不同的临床疾病和生物学过程。在初步工作中，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，并证明可以可靠地识别四种LSCC亚型。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）。我们假设四种先验LSCC亚型是强大的生物学疾病，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检测。UNC队列亚型将通过历史队列进行预测，并通过内部UNC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性区域：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UNC队列基因组拷贝数，通过SNP微阵列测量。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方法来预测临床组织标本的LSCC亚型。然后，我们将在一个大型独立队列中使用我们的检测方法来预测LSCC亚型，并评估LSCC亚型是否具有不同的临床病程，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LSCC分子分类可能有助于解释这种疾病的各种临床结果，并为新的专业治疗提供基础。通过该提案开发的检测将允许临床标本中的LSCC亚型鉴定，并且是常规临床诊断的一步。亚型特异性基因组拷贝数畸变可能有助于LSCC的病因模型。

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.