TOWARD A MOLECULAR CLASSIFICATION OF HUMAN ASTROCYTOMAS

描述（改编自申请人的摘要）：星形细胞瘤是最常见的肿瘤。 常见的中枢神经系统原发性肿瘤。 但 星形细胞瘤的分类和分级仍有争议， 治愈性疗法仍然难以捉摸。 例如，最恶性的形式 星形细胞瘤，多形性胶质母细胞瘤，在其 病理学及其对各种治疗的反应，但组织病理学 方案还不能将胶质母细胞瘤细分为亚组 反映预后或治疗反应。 的初步数据 实验室的研究人员现在认为，分子遗传分析可能 提供了一种更好的星形细胞肿瘤亚分类的方法。 之一 因此，该提案的主要目标是探索潜在的 分子探针作为替代诊断工具， 这种分子遗传学工具可以提供一种遗传学的方法， 与预后相关性更好的分类系统， 治疗反应比目前的分类方案。 与这一目标密切相关的是，调查人员建议查明， 分离和鉴定染色体上特异性"肿瘤抑制"基因 10和17 p，被认为在星形细胞瘤肿瘤发生中起关键作用。 可能为肿瘤的基本机制提供重要的新见解 星形细胞瘤和其他人类肿瘤的发生和组织发生 癌症，这对他们的诊断和治疗都有潜在的重要意义。 和治疗。 因此，为了全面了解最重要的 在多种星形细胞肿瘤中染色体缺失， 研究人员将为不同的星形细胞瘤产生一个"等位基因型"， 恶性等级，使用一组高度多态性的DNA标记， 每条染色体的每条臂，包括已知的"肿瘤抑制基因"的标记物 的位点 根据他们的初步数据，可能有不止一个"肿瘤"， 10号和17号染色体上的"抑制基因"位点。 他们将进一步 缩小并包围染色体10和17上的缺失区域，以及 可能识别这些细胞中包含的"肿瘤抑制"基因， 删除。 他们将证实他们的初步观察， 10号染色体缺失与短染色体缺失呈负相关 胶质母细胞瘤中17号染色体臂（17p），表明存在 胶质母细胞瘤的不同基因亚型。 此外，他们将 特别是17p上的p53 "肿瘤抑制"基因在 星形细胞瘤发展的不同阶段。 他们的初步数据 这表明EGF受体的扩增与EGF受体的缺失有关。 10号染色体，但17号染色体不缺失。 能够检查一个较大的 EGF受体拷贝的原发性和复发性标本数量 数字可以阐明这种畸变是否描绘了一个独特的子集 星形细胞瘤 最后，所有上述遗传畸变将被关联a） 许多组织病理学分级方案，如WHO和Daumas- Duport分类以及个体组织病理学 特征，和B）长期临床数据，包括预后 （生存、复发）和对某些类型治疗的反应 （化疗、放疗）。 这可能最终导致 星形胶质细胞的不同生物学和遗传学亚型的确定 与预后和治疗相关的肿瘤比 传统分类。

DESCRIPTION (Adapted from Applicant's Abstract):Astrocytomas are the most common primary tumors of the central nervous system. However, the classification and grading of astrocytomas remains controversial and curative therapies remain elusive. For instance, the most malignant form of astrocytoma, the glioblastoma multiforme, is heterogeneous in its pathology and in its response to various therapies, yet histopathologic schemes have not been able to subclassify glioblastomas into subgroups that reflect prognosis or therapeutic response. Preliminary data from the investigators laboratory now suggest that molecular genetic analysis may provide a means of better sub- classifying astrocytic tumors. One of the major objectives of this proposal, therefore, is to explore the potential of molecular probes as alternative diagnostic tools in the assessment of astrocytic tumors.Such molecular genetic tools may provide for a genetic classification system which correlates better with prognosis and therapeutic response than do current classification schemes. In close connection with this goal, the investigators propose to identify, isolate, and characterize specific "tumor suppressor" genes on chromosomes 10 and 17p, thought to play a key role in astrocytoma tumorigenesis.This may provide critical new insights into fundamental mechanisms of tumor development and histogenesis in astrocytomas and possibly other human cancers, with potentially important implications for both their diagnosis and treatment. Thus, to obtain a comprehensive overview of the most significant chromosome deletions in a wide variety of astrocytic tumors, the investigators will generate an "allelotype" for astrocytomas of different malignancy grades, using a battery of highly polymorphic DNA markers for each arm of each chromosome, including markers to known "tumor suppressor" loci. Based on their preliminary data, there may be more than one "tumor suppressor" locus on both chromosomes 10 and 17p. They will further narrow and bracket the deleted regions on chromosomes 10 and 17, and possibly identify the "tumor suppressor" genes contained in these deletions. They will substantiate their preliminary observation of a negative correlation between loss of chromosome 10 and loss of the short arm of chromosome 17 (17p) in glioblastomas, suggesting the existence of distinct genetic subtypes of glioblastoma. Furthermore, they will specifically address the role of the p53 "tumor suppressor" gene on 17p in different stages of astrocytoma development. Their preliminary data suggest that EGF receptor amplifications are correlated with loss of chromosome 10, but not with loss of 17p. The ability to examine a larger number of both primary and recurrent specimens for EGF receptor copy number may elucidate whether this aberration delineates a distinct subset of astrocytomas. Finally, all above mentioned genetic aberrations will be correlated a) with a number of histopathologic grading schemes such as WHO and Daumas- Duport classifications, as well as with individual histopathologic features, and b) with long term clinical data, including prognosis (survival, recurrence) and response to certain types of treatment (chemotherapy, radiotherapy). This may eventually lead to the determination of distinct biological and genetic subtypes of astrocytic tumors that better correlate with prognosis and treatment than do traditional classifications.