MYC as a Biomarker in Aggressive Non-Hodgkin Lymphoma

 描述(申请人提供)：MYC作为侵袭性非霍奇金淋巴瘤项目的生物标记物摘要非霍奇金淋巴瘤(NHL)是最常见的血液系统恶性肿瘤，约占人类癌症的4.6%，导致美国约3.5%的癌症死亡。非霍奇金淋巴瘤在美国的发病率在1975至1991年间增加了80%以上--是所有癌症中增幅最大的之一(SEER癌症统计报告1975-2004)。虽然NHL有50多种类型，但弥漫性大B细胞淋巴瘤(DLBCL)是最常见的，约占所有NHL的35%。在美国，每年每10万人中约有7人受到DLBCL的影响。一半的DLBCL患者不能用标准的利妥昔单抗、环磷酰胺、阿霉素、长春新碱和强的松(R-CHOP)治疗。目前判断DLBLC预后的最常用工具是国际预后指数(IPI)，它基于五个临床特征(患者年龄、肿瘤分期、血清乳酸脱氢酶浓度、表现状态和结外病变部位数)。然而，IPI评分相同的患者在生存方面表现出显著的变异性，这表明在每一种IPI类别中存在显著的残余异质性。通过易位、扩增或其他机制解除对编码c-Myc转录因子的MYC基因的调控在 淋巴系恶性肿瘤的发病机制，包括DLBCL。我们已经与25个医疗中心组成了一个国际DLBCL R-CHOP联盟，并建立了自己作为DLBCL生物标记物专业团队的领先地位。我们假设MYC是DLBCL预后和风险调整治疗的生物标志物。在这一应用中，我们提出了三个目的，以确定MYC的遗传和非遗传改变在DLBCL预后和治疗中的潜力。在目标1中，我们将使用3,000例标本来确定MYC在DLBCL预后中的综合作用。在目标2中，我们将确定有MYC易位的DLBCL和没有MYC易位的DLBCL在基因表达和治疗反应方面是否存在差异。在目标3中，我们将确定DLBCL中MYC CDS和3‘UTR突变的不同预后价值的分子基础。

 DESCRIPTION (provided by applicant): MYC as a Biomarker in Aggressive Non-Hodgkin Lymphoma Project Abstract Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy, constituting about 4.6% of human cancers and causing about 3.5% of all cancer deaths in the United States. The incidence of NHL has increased by more than 80% between 1975 and 1991 in the United States - one of the largest increases of any cancer (SEER Cancer Statistics Review 1975-2004). Although there are more than 50 types of NHLs, diffuse large B cell lymphoma (DLBCL) is the most common, accounting for approximately 35 percent of all NHLs. In the United States, DLBCL affects about 7 out of 100,000 people each year. Half of DLBCL patients cannot be cured with the standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Currently the most common tool for determining DLBLC prognosis is the International Prognostic Index (IPI), which is based on five clinical characteristics (patient age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites). Yet patients with identical IPI scores exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each IPI category. Deregulation of MYC, the gene that encodes the c-Myc transcription factor, through translocation, amplification, or other mechanisms is important in the pathogenesis of lymphoid malignancies, including DLBCL. We have assembled an International DLBCL R-CHOP Consortium with 25 medical centers and have established ourselves as a leading team specializing in DLBCL biomarkers. We hypothesize that MYC is a biomarker for DLBCL prognosis and risk-adjusted therapies. In this application, we propose three aims to ascertain the potential of genetic and non-genetic alteration of MYC in DLBCL prognosis and therapy. In Aim 1, we will determine the comprehensive role of MYC in DLBCL prognosis using 3,000 specimens. In Aim 2, we will determine whether DLBCL with MYC translocation differs from those without MYC translocation in gene expression and treatment response. In Aim 3, we will determine the molecular basis of differential prognostic values of MYC CDS and 3'UTR mutations in DLBCL.