The coding genome of HIV-associated plasmablastic lymphomas in South Africa

南非 HIV 相关浆母细胞淋巴瘤的编码基因组

• 批准号: 8841047
• 负责人: Laura Pasqualucci
• 金额: $ 19.75万
• 依托单位: WITS HEALTH CONSORTIUM (PTY), LTD
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841047
• 关键词: AIDS/HIV problem; Accounting; African; Archives; Area; B-Cell Lymphomas; BRAF gene; Biological Markers; Burkitt Lymphoma; CREBBP gene; Chromosomal translocation; Chronic Lymphocytic Leukemia; Code; Collection; Complication; Data; Diagnosis; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Disease; Fluorescent in Situ Hybridization; Follicular Lymphoma; Frequencies; Gene Fusion; Gene Targeting; Genes; Genetic; Genomics; HIV; HIV Genome; HIV Infections; HIV Seropositivity; Hairy Cell Leukemia; Immunocompetent; Immunologic Deficiency Syndromes; Incidence; Individual; Knowledge; Large-Cell Immunoblastic Lymphoma; Lesion; Life; Lymphoma; Malignant Neoplasms; Mature B-Lymphocyte; Molecular; Molecular Target; Morbidity - disease rate; Mutation; NOTCH1 gene; Normal tissue morphology; Pathogenesis; Pathology; Pathway interactions; Patients; Pleural effusion disorder; Point Mutation; Population; Positioning Attribute; Prevalence; RNA; RNA Sequences; Sampling; Sequence Analysis; Single Nucleotide Polymorphism; South Africa; Targeted Resequencing; Technology; Therapeutic; Therapeutic Intervention; Universities; cancer type; cohort; deep sequencing; differentiated B cell; exome; exome sequencing; genome-wide; high throughput technology; improved; instrument; large cell Diffuse non-Hodgkin' s lymphoma; lymphoid neoplasm; mortality; novel; prognostic; public health relevance; screening; transcriptome sequencing; tumor

 DESCRIPTION (provided by applicant): Plasmablastic lymphoma (PBL) is a highly aggressive lymphoma of pre-terminally differentiated B-cells which is often associated with HIV/AIDS immunodeficiency and represents one of the two B-NHL diagnoses that have significantly increased in incidence in South Africa over the past few years. This tumor has well documented morphological and immunophenotypic features but the specific mutational signature associated with HIV-associated PBL is unknown. This project aims to identify cancer driver genes by integrating diverse genomic data to interrogate a panel of 20 PBL and matched normal tissues for the presence of somatic point mutations, copy number alterations and genes fusion. Genomic data from this cohort will be integrated to assess the most likely driver genes using MutComfocal, and representative significant lesions will be validated in the same cases by FISH and Sanger sequencing analysis. The prevalence of genetic lesions at the top 30 candidate target genes will be assessed in a screening panel of 100 HIV associated PBL cases by targeted resequencing in the Illumina MiSeq instrument and FISH analysis. These data will then be contrasted to the genetic landscape of HIV negative DLBCL, by using exome sequencing and SNP array data generated by our team in previous studies. The results of the proposed studies are expected to further our knowledge about the molecular pathogenesis of PBL and have the potential to uncover novel molecular targets/pathways that are disrupted by genetic lesions in this disease and may be exploited as biomarkers for improved diagnostic, prognostic and/or therapeutic management of this aggressive disease.

 描述（由适用提供）：浆膜淋巴瘤（PBL）是末端分化的B细胞的高度攻击性淋巴瘤，通常与HIV/AIDS免疫缺陷有关，并且代表了过去几年中南非的两种B-NHL诊断之一。该肿瘤的形态和免疫表型特征有充分的文献证明，但是与HIV相关的PBL相关的特定突变特征尚不清楚。该项目旨在通过整合潜水员基因组数据来审问一个20 PBL的面板，并匹配正常组织，以识别癌症驱动基因，并匹配正常组织，以存在体细胞突变，拷贝数改变和基因融合。来自该队列的基因组数据将集成以评估使用MutComfocal的最可能的驱动基因，并且在同一情况下，通过FISH和Sanger测序分析来验证代表重大病变。将在Illumina Miseq仪器和鱼类分析中靶向重新方程，在100 HIV相关的PBL病例的筛查面板中评估遗传病变的患病率。然后，通过使用我们的团队在先前的研究中生成的外显子组测序和SNP阵列数据，这些数据将与HIV阴性DLBCL的遗传景观形成鲜明对比。拟议的研究的结果有望进一步提高我们对PBL分子发病机理的了解，并有可能发现该疾病中受遗传病变破坏的新型分子靶标/途径，并且可以作为生物标志物作为生物标志物，以不良诊断，预后和/或这种侵略性疾病的治疗管理。