MOLECULAR CLASSIFICATION OF B-CELL LYMPHOMA

来源于相同细胞类型和具有相似形态的肿瘤可能有明显不同的临床行为和对治疗的反应。这些肿瘤的基因表达谱所反映的遗传病变的差异，将为观察到的不同临床谱的潜在机制提供见解。比较基因组杂交（CGH）和光谱核型（SKY）是高度互补的新技术，可以检查整个基因组的遗传异常，并可以补充和扩展传统的细胞遗传学研究。此外，最近发展起来的高密度cDNA微阵列技术是一种很有前途的显示肿瘤组织中基因表达模式的方法。这些强大的技术及其相关的信息系统现在可用于转译研究。为了评估这些技术产生的信息，必须有足够数量的具有详细临床数据的特征明确的肿瘤。我们提出了一个多机构，全面的分子分析大系列的b细胞非霍奇金淋巴瘤（NHL）。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，以确定临床和生物学上不同的B- NHL亚群。当临床和生物学意义的独特分子谱被确定后，我们将定义每个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和涉及这些基因的细胞遗传学异常进行特定的确证性检测。我们的长期目标是利用这些信息设计一种更简单、更便宜的用于诊断的微阵列。这种“诊断芯片”可以在每个B-NHL出现时提供快速的分子表征，以获得最佳治疗决策和预后。我们还期望发现新的和重要的遗传改变，这将有助于我们理解肿瘤转化和肿瘤进展的关键事件。从这个项目中获得的见解也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.