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（由申请人提供）：浆母细胞淋巴瘤（PBL）是一种高度侵袭性的终末前分化B细胞淋巴瘤，通常与HIV/AIDS免疫缺陷相关，是过去几年在南非发病率显著增加的两种B-NHL诊断之一。该肿瘤具有良好的形态学和免疫表型特征，但与HIV相关PBL相关的特异性突变特征尚不清楚。该项目旨在通过整合不同的基因组数据来鉴定癌症驱动基因，以询问一组20个PBL和匹配的正常组织是否存在体细胞点突变，拷贝数改变和基因融合。将整合来自该队列的基因组数据，以使用MutComfocal评估最可能的驱动基因，并通过FISH和桑格测序分析在相同病例中验证代表性显著病变。通过Illumina MiSeq仪器中的靶向重测序和FISH分析，在100例HIV相关PBL病例的筛选组中评估前30个候选靶基因处遗传病变的患病率。然后将这些数据与HIV阴性DLBCL的遗传景观进行对比，通过使用我们团队在以前的研究中生成的外显子组测序和SNP阵列数据。拟议的研究的结果预计将进一步我们的知识PBL的分子发病机制，并有可能发现新的分子靶点/途径，在这种疾病中的遗传病变被破坏，并可能被利用作为生物标志物，以改善诊断，预后和/或治疗管理这种侵略性疾病。