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

 描述(申请人提供)：浆母细胞性淋巴瘤(PBL)是一种高度侵袭性的终末分化前B细胞淋巴瘤，通常与艾滋病毒/艾滋病免疫缺陷有关，是过去几年南非发病率显著上升的两种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相关的PBL相关的特定突变特征尚不清楚。该项目旨在通过整合不同的基因组数据来询问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，从而识别癌症驱动基因。来自这个队列的基因组数据将被整合，以使用MutComocus评估最有可能的驱动基因，在相同的病例中，具有代表性的重大病变将通过FISH和Sanger测序分析得到验证。通过Illumina MiSeq仪器中的定向重测序和FISH分析，将在一个由100例艾滋病毒相关PBL病例组成的筛查小组中评估前30个候选目标基因的遗传损伤的流行率。然后，通过使用我们的团队在以前的研究中产生的外显子组测序和SNP阵列数据，将这些数据与HIV阴性的DLBCL的遗传格局进行对比。这些研究的结果有望进一步加深我们对PBL分子发病机制的认识，并有可能发现新的分子靶点/通路，这些靶点/通路可被这种疾病的遗传损害破坏，并可能被用作改善这种侵袭性疾病的诊断、预后和/或治疗的生物标志物。

 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.