Molecular diagnosis and outcome prediction in lymphoma

淋巴瘤的分子诊断和结果预测

• 批准号: 7733410
• 负责人: Louis Staudt
• 金额: $ 77.05万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733410
• 关键词: 3' Untranslated Regions; Accounting; B-Cell Lymphomas; B-Lymphocytes; Behavior; Biological; Cell Proliferation; Clinical; Cyclin D1; Diagnosis; Diagnostic Procedure; Diffuse Lymphoma; Disease; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genomics; Half-Life; Heterogeneity; Human; Inferior; Laboratories; Length; Life; Lymphoma; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Mediastinal; Messenger RNA; Molecular Diagnosis; Molecular Profiling; Mutation; NF-kappa B; Numbers; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Point Mutation; Polyadenylation; Range; Receptors, Antigen, B-Cell; Relative (related person); Signal Transduction; Somatic Mutation; Staging; Standards of Weights and Measures; Structure of germinal center of lymph node; Survival Rate; Terminator Codon; Trisomy 3; Tumor Suppressor Proteins; Untranslated Regions; base; chemotherapy; comparative genomic hybridization; large cell Diffuse non-Hodgkin' s lymphoma; lymphoid neoplasm; mRNA Expression; novel; outcome forecast; response; scaffold; tumor

On the basis of gene expression profiling, the laboratory proposed that the most common form of lymphoma, diffuse large B cell lymphoma (DLBCL), is a composite of three molecularly distinct diseases that are indistinguishable by standard diagnostic methods. These diseases, termed germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL), arise from B lymphocytes at different stages of differentiation by distinct oncogenic pathways. The curative response of patients with DLBCL to chemotherapy is highly variable, and the DLBCL subtype distinction accounts, in part, for this heterogeneity. With CHOP multi-agent chemotherapy, the 5-year survival rates of ABC DLBCL and GCB DLBCL are 60% and 30%, respectively. This clinical disparity likely reflects the host of genetic differences between these DLBCL subtypes. Array-based comparative genomic hybridization was used to identify genomic changes in copy number that influenced survival. Two genomic alterations that occurred exclusively in ABC DLBCL were deletion of the INK4a/ARF tumor suppressor locus and trisomy 3. These genetic aberrations, considered separately and together, identified a subset of patients with ABC DLBCL with inferior prognosis relative to other patients with this DLBCL subtype. This ABC DLBCL subset was also characterized by oncogenic mutations in the CARD11 gene, which encodes a scaffold molecule required for NF-kB signaling downstream of the B cell receptor. These mutations are responsible for constitutive NF-kB activity in ABC DLBCLs. The co-occurrence of CARD11 mutations, INK4a/ARF locus deletions and trisomy 3 in a subset of ABC DLBCLs suggests that this subset may arise by a distinct pathogenetic pathway. Mantle cell lymphoma is a disease with a highly variable clinical course, with some patients living 5 or more years and other succumbing to the disease in under 1 year. The Staudt laboratory previously discovered that a gene expression signature of cellular proliferation was the single dominant predictor of length of survival following diagnosis of mantle cell lymphoma. One mechanism responsible for the increased proliferation of some mantle cell lymphoma tumors is increased expression of cyclin D1, which is characteristically translocated in this disease. The Staudt laboratory demonstrated that variability in cyclin D1 mRNA in mantle cell lymphoma was due to somatic alterations in the 3 untranslated region (UTR) of the mRNA. The 3UTR of cyclin D1 contains a sequence that destabilizes the cyclin D1 mRNA. The Staudt laboratory deletions encompassing this region in some cases with high cyclin D1 mRNA expression. A novel form of somatic mutation was identified in other such cases in which point mutations following the stop codon created new polyadenylation and cleavage signals, resulting in expression of a short cyclin D1 mRNA lacking the destabilization motif. As expected, these short cyclin D1 mRNAs accumulated to higher levels due to their prolonged half-life.

在基因表达分析的基础上，实验室提出，淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）最常见的形式是三种分子不同疾病的复合物，这些疾病是由标准诊断方法无法区分的。这些疾病称为生殖中心B细胞（GCB）DLBCL，激活的B细胞样（ABC）DLBCL和原发性纵隔B细胞淋巴瘤（PMBL），是由B淋巴细胞在不同阶段在不同阶段通过不同的致癌途径在不同阶段的B淋巴细胞引起的。 DLBCL患者对化学疗法的治疗反应高度可变，而DLBCL亚型的区别部分则部分是这种异质性。通过CHOP多药化疗，ABC DLBCL和GCB DLBCL的5年生存率分别为60％和30％。这种临床差异可能反映了这些DLBCL亚型之间的遗传差异。基于阵列的比较基因组杂交用于确定影响生存的拷贝数的基因组变化。 ABC DLBCL中仅发生的两种基因组改变是INK4A/ARF肿瘤抑制基因座和三体肌3的缺失。这些遗传像差被认为分别和一起识别为ABC DLBCL患者的一部分，与此DLBCL亚型相对于其他患者，ABC DLBCL患者的预后较低。该ABC DLBCL子集也以Card11基因中的致癌突变为特征，该基因编码B细胞受体下游NF-KB信号所需的支架分子。这些突变负责ABC DLBCL中的组成型NF-KB活性。 Card11突变，Ink4a/ARF基因座缺失和三体三体中的Card11突变的共发生，这表明该子集可能是由独特的致病途径引起的。地幔细胞淋巴瘤是一种疾病，患有高度可变的临床病程，有些患者的生活5年或更长时间，而另一些患者则在1年内屈服于该疾病。 Staudt实验室先前发现，细胞增殖的基因表达特征是地幔细胞淋巴瘤诊断后生存时间长度的单个主要预测指标。导致某些地幔细胞淋巴瘤肿瘤增殖增加的一种机制是细胞周期蛋白D1的表达增加，这在该疾病中特征是易位的。 Staudt实验室表明，地幔细胞淋巴瘤中细胞周期蛋白D1 mRNA的变异性是由于mRNA的3个未翻译区（UTR）的体细胞改变引起的。细胞周期蛋白D1的3UTR包含一个破坏细胞周期蛋白D1 mRNA的序列。在某些情况下，Cyclin D1 mRNA表达的staudt实验室缺失包含该区域。在其他这样的情况下，鉴定出一种新型的体细胞突变形式，在终止密码子之后的点突变产生了新的聚腺苷酸化和裂解信号，从而表达了短的细胞周期蛋白D1 mRNA缺乏不稳定基序。如预期的那样，由于其长时间寿命长，这些短的细胞周期蛋白D1 mRNA积累到更高的水平。