Prognostic Models in Diffuse Large B-Cell Lymphoma

描述（由申请人提供）：弥漫性大b细胞淋巴瘤（DLBCL）具有明显的生物学和临床异质性。在chop时代，研究表明可以通过测量有限数量基因的表达来预测DLBCL患者的生存。然而，标准治疗已经发展到包括利妥昔单抗和CHOP。初步研究表明，利妥昔单抗的加入改变了特定分子生物标志物的预测能力，与利妥昔单抗抗肿瘤作用相关的新生物标志物可能具有预后意义。因此，迫切需要建立可靠的基于生物标志物的DLBCL患者预后模型，这将有可能改变我们的医学实践方式。此外，所有先前的模型都是基于冷冻标本中的RNA测量，其可用性有限，从而限制了所提出的预后模型的适用性。基于广泛使用的石蜡包埋样本，使用RNA或免疫组织化学分析基因表达，构建预后模型将使这些模型在日常临床实践中立即广泛适用。

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) is characterized by marked biological and clinical heterogeneity. In the CHOP-era, it was demonstrated that survival of DLBCL patients can be predicted by measurement of expression of a limited number of genes. However, the standard treatment has evolved to include the rituximab with CHOP. Initial studies suggest that addition of rituximab changes the predictive power of specific molecular biomarkers and it is possible that new biomarkers associated with the anti-tumor effects of rituximab may become prognostically significant. Therefore, there is an urgent need to establish reliable biomarker-based prognostic models for DLBCL patients treated with the current standard regimen of R-CHOP, which will potentially change the way we practice medicine. In addition, all the previous models were based on RNA measurement in frozen specimens, which availability is limited thus restricting applicability of the proposed prognostic models. Construction of prognostic models based on widely available paraffin embedded samples using either RNA or immunohistochemistry for analysis of gene expression would allow immediate and widespread applicability of these models in daily clinical practice. This project is based on a new methodology of RNA extraction from formalin-fixed, paraffin-embedded tissues, developed in our laboratory, which allows reliable measurement of gene expression by either real-time PCR or oligo-microarrays. This methodology will be used to accomplish the goals of this project that include: 1. Identify a list of genes which expression correlates with survival of DLBCL patients treated with R-CHOP by array-based gene expression profiling; 2. Construct and validate a paraffin-based real-time PCR gene expression prognostic mode based on RNA derived from paraffin specimens; 3. Examine the survival predictive power of biomarkers associated with the anti-tumor effects of rituximab in DLBCL patients treated with R-CHOP; 4. Construct a prognostic model for DLBCL patients treated with R-CHOP based on the expression of a limited set of genes measured at the protein level by immunohistochemistry. These studies should define paraffin-based molecular prognostic models for most common type of lymphoma that will be used in clinical practice and will add to the prognostic power of the current clinical prognostic indexes. Routine application of the prediction models will enable identification of patients at high risk for standard therapy failure and may form the basis for risk-adjusted therapies for DLBCL. Furthermore, identification of genes-proteins comprising the predictive models will point to distinct pathogenesis mechanisms of DLBCL subtypes and potentially lead to recognition of new molecular therapeutic targets. Further, establishment of a paraffin-based RNA prognostic model using the new methodology of RNA extraction could serve as a paradigm for other lymphomas and tumors.