MOLECULAR CLASSIFICATION OF B-CELL LYMPHOMA

来自相同细胞类型和具有相似形态的肿瘤可能会有明显不同的临床行为和治疗反应。这些肿瘤中遗传损伤的差异，如它们的基因表达谱所反映的，将提供对所观察到的不同临床谱系背后的机制的洞察。比较基因组杂交(CGH)和光谱核型分析(SKY)是高度互补的新技术，可以检查整个基因组的遗传异常，可以补充和扩展传统的细胞遗传学研究。此外，新近发展起来的高密度基因芯片技术是显示肿瘤组织中基因表达模式的一种非常有前途的方法。这些强大的技术及其相关的信息系统现在可用于翻译研究。为了评估这些技术产生的信息，必须有足够数量的具有良好特征的肿瘤和详细的临床数据。我们建议对一大系列B细胞非霍奇金淋巴瘤(NHL)进行多机构、全面的分子分析。获得的分子数据将与我们机构保存的广泛数据库中的临床和病理信息相关联，以识别临床和生物学上不同的B-NHL亚型。当确定了具有临床和生物学意义的独特分子图谱时，我们将确定每个图谱中的哪些成分是临床特征和结果的基本决定因素。将对关键基因的表达以及涉及这些基因的细胞遗传学异常进行特定的验证性分析。我们的长期目标是利用这些信息设计一种更简单、更便宜的诊断用微阵列。这种“诊断芯片”可以在展示时快速提供每一种B-NHL的分子特征，以便做出最佳的治疗决策和预测。我们还期待新的和重要的基因改变的识别，这将有助于我们理解肿瘤转化和肿瘤进展的关键事件。从该项目中获得的见解还可能为预防和治疗干预确定新的目标。

Tumors derived from the same cell type and having similar morphology may nevertheless have a distinctly different clinical behavior and response to therapy. Differences in the genetic lesions in these tumors, as reflected by their gene expression profiles, will provide insight into the mechanisms underlying the divergent clinical spectrum that is observed. Comparative genomic hybridization (CGH) and spectral karyotyping (SKY) are highly complementary novel techniques that examine the entire genome for genetic abnormalities and can supplement and extend conventional cytogenetic studies. In addition, the recently - developed high-density cDNA microarray technology is a very promising method for displaying the pattern of gene expression in tumor tissues. These powerful technologies with their associated informatic systems are now available for translational research. In order to evaluate the information generated by these technologies, an adequate number of well-characterized tumors with detailed clinical data must be available. We propose a multi-institutional, comprehensive molecular analysis of a large series of B-cell non-Hodgkin's lymphoma (NHL). The molecular data obtained will be correlated with the clinical and pathologic information in the extensive databases kept at our institutions to identify clinically and biologically distinct subsets of B- NHL. When unique molecular profiles of clinical and biological significance are identified, we will then define which components within each profile are essential determinants of the clinical features and outcome. Specific confirmatory assays for the expression of key genes, and the cytogenetic abnormalities involving these genes, will be performed. Our longer term goal is to use this information to design a simpler and less expensive microarray for diagnostic use. This "diagnostic chip" could provide rapid molecular characterization of every B-NHL at presentation for optimal treatment decisions and prognostication. We also anticipate the identification of new and significant genetic alterations that will contribute to our understanding of the key events in neoplastic transformation and tumor progression. The insights gained from this project may also identify novel targets for preventive and therapeutic interventions.