Toward a molecular classification of human gliomas

描述（由申请人提供）：常见恶性胶质瘤的病理分类问题使预测患者预后和治疗反应复杂化。 这项研究的长期目标是提供一个全面的理解，神经胶质瘤肿瘤发生的特征性遗传事件，并引入遗传分析到常规分类。 在该基金的前两个资助期内，我们已经阐明了神经胶质瘤形成的遗传事件，将基因型与临床病理参数相关联，并将遗传分析引入临床实践。 这项工作现在提出了三个假设，可以使用经过验证的翻译研究策略进行测试。 1)为了检验这一假设，分子概况可以分为组织学经典和非经典的恶性胶质瘤改善预后和预测亚组在一个实用的方式，我们建议定义标记物能够强大的区分化疗敏感性和预后较好的恶性胶质瘤化疗耐药和预后不良的恶性胶质瘤。 2)为了检验这一假设，即增加的细胞侵袭与预后无关的组织学表现，这样的分子表型可以很容易地检测到，我们建议定义一个“入侵基因型/表型”，与恶性胶质瘤患者的临床病理学终点。 3)最后，为了验证这一假设，即持续的选择压力决定肿瘤基因型，分子诊断方法应考虑到这种异质性，我们建议描述胶质母细胞瘤周围坏死性假alisades的瘤内选择，以定义与间变性星形细胞瘤患者临床病理终点相关的分子特征。 因此，每个目标都测试了一个相关的假设，即特定的分子分析可以增强目前的胶质瘤分类方法，每个目标也遵循类似的实验设计。 进一步阐明人类胶质瘤的遗传基础将继续有助于胶质瘤分类系统，这将更准确地反映肿瘤的行为和治疗反应比目前的组织病理学方案。

DESCRIPTION (provided by applicant): Problems in the pathological classification of the common malignant gliomas complicate predicting patient prognosis and response to therapy. The long-term goal of this research is to provide a comprehensive understanding of the genetic events that characterize glioma tumorigenesis and to introduce genetic analyses into routine classification. During the two prior funding periods of this grant, we have clarified genetic events that underlie glioma formation, have correlated genotype with clinicopathological parameters, and have introduced genetic analyses into clinical practice. This work now raises three hypotheses that can be tested using proven translational research strategies. 1) To test the hypothesis that molecular profiles can divide histologically classic and non-classic malignant gliomas into improved prognostic and predictive subgroups in a practical manner, we propose to define markers capable of robust distinction of chemosensitive and better prognosis malignant gliomas from chemoresistant and poor prognosis malignant gliomas. 2) To test the hypothesis that increased cellular invasion correlates with prognosis independent of histological appearance and that such a molecular phenotype can be readily detected, we propose to define an "invasion genotype/phenotype" that correlates with clinicopathological endpoints in patients with malignant gliomas. 3) Finally, to test the hypothesis that ongoing selection pressures operate to determine tumor genotype, and that molecular diagnostic approaches should take such heterogeneity into account, we propose to characterize intratumoral selection in glioblastoma perinecrotic pseudopalisades to define a molecular signature that correlates with clinicopathological endpoints in patients with anaplastic astrocytomas. Each aim thus tests a related hypothesis that a particular molecular analysis can augment current approaches to glioma classification, and each aim also follows a similar experimental design. The further clarification of the genetic basis of human gliomas will continue to contribute to a glioma classification system that will more accurately reflect tumor behavior and response to therapy than current histopathological schemes.