Comprehensive identification of fusion transcripts in leukemia

白血病融合转录本的综合鉴定

• 批准号: 7825127
• 负责人: JANET D ROWLEY
• 金额: $ 50万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825127
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Area; Cancer Etiology; Candidate Disease Gene; Cells; Classification; Clinical; Complementary DNA; Computer Analysis; DNA; Data; Detection; Diagnosis; Disease; Early Diagnosis; Fingerprint; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Markers; Genome; Genomics; Goals; Hand; Informatics; Karyotype; Malignant Neoplasms; Maps; Messenger RNA; Methods; Mutation; Outcome; Play; Preparation; Process; Reading; Resources; Role; Sampling; Solid Neoplasm; Specificity; Structure; Techniques; Transcript; abstracting; cancer genetics; cancer genome; cancer therapy; clinical Diagnosis; clinical application; cost; fusion gene; insertion/deletion mutation; leukemia; next generation; novel marker; outcome forecast; public health relevance; structural genomics; tool

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics, and Specific Challenge Topic 03-CA-101 Fingerprints for the Early Detection and Treatment of Cancer. Project Summary /Abstract Chromosomal structural aberration includes translocation, inversion, insertion, and deletion. Such changes could directly disrupt the structure of normal genes and form fusion genes between two genes. Such changes have been well demonstrated in leukemia and increasingly revealed in solid tumors as well. Many chromosomal structural aberrations have been demonstrated to play important roles in tumorogenesis, and used widely as genetic markers in clinical applications including diagnosis, treatment and prognosis. Although great progress has been made, we are still far away from comprehensive understanding of the spectrum of structural aberrations in a cancer genome. In many cancers, genetic structural changes have not been identified. Those unknown genetic mutations could have specific structural features or affect smaller loci that may be difficult to identify using the conventional techniques. On the other hand, for the genetic structural aberrations already identified, it is still difficult to distinguish between the "passenger" mutations that are not the causes of the cancer but random mutations following the process of tumorogenesis, and the "driver" mutations that directly contribute to tumorogenesis. mRNA is the functional readouts of the active genes in the cell under a given condition. The presence of fusion transcripts between unrelated mRNAs may provide direct evidence for the presence of the genomic structural aberration in the genome, and for its functional involvement in tumorogenosis, which is critical in distinguishing the "driver" mutation from the "passenger" mutation. The recently developed RNA-Seq method provides a powerful tool for detecting the fusion transcripts. It only needs simple sample preparation and can collect massive short cDNA sequences from the next-generation DNA sequencers at low cost. The large quantity of sequences provides rich resources for comprehensive identification of fusion transcripts and their original genomic aberrations. In this proposal, we plan to perform a systematic analysis for the fusion transcripts and their chromosomal structural aberrations in AML (acute myeloid leukemia), a major type of leukemia. Although consistent chromosomal structural changes have been identified in AML, half of AML cases do not contain those known chromosomal structural aberrations. The clinical outcomes of these AML cases differ from those with known translocations, suggesting that the normal karyotype AML may contain different genetic aberrations. In this proposal, we plan to use the RNA-Seq method to obtain a comprehensive transcriptome from 50 AML samples. We plan to perform extensive informatics analysis to identify the fusion transcripts and other changes in order to locating their original structural aberrations in the disease genome. The potential impact of the study will be to provide a comprehensive map of fusion and genetic aberrations in AML, to identify new candidate genes involved in AML, to provide new candidate genes for identifying the "driver" mutations, and to provide new genetic markers for cancer subtype classification and for better diagnosis, treatment and prognosis of AML PUBLIC HEALTH RELEVANCE: The proposal plans to perform a comprehensive detection of fusion transcripts in acute myeloid leukemia, with the aims to identify new genes contributing to this disease and to identify new markers for clinical diagnosis, treatment and prognosis of this disease.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (08) 基因组学，以及用于癌症早期检测和治疗的具体挑战主题 03-CA-101 指纹。 项目概要/摘要 染色体结构畸变包括易位、倒位、插入和缺失。这种变化可以直接破坏正常基因的结构，并在两个基因之间形成融合基因。这种变化已在白血病中得到充分证明，并且在实体瘤中也越来越多地显现出来。许多染色体结构畸变已被证明在肿瘤发生中发挥重要作用，并作为遗传标记广泛应用于临床应用，包括诊断、治疗和预后。 尽管已经取得了巨大进展，但我们距离全面了解癌症基因组结构畸变谱系还很遥远。在许多癌症中，遗传结构变化尚未确定。这些未知的基因突变可能具有特定的结构特征或影响使用传统技术可能难以识别的较小基因座。另一方面，对于已经发现的基因结构畸变，仍然很难区分不是癌症原因而是肿瘤发生过程中随机突变的“过客”突变和直接促成肿瘤发生的“驱动”突变。 mRNA 是给定条件下细胞中活性基因的功能读数。不相关mRNA之间融合转录物的存在可能为基因组中基因组结构畸变的存在及其在肿瘤发生中的功能参与提供直接证据，这对于区分“驱动”突变和“乘客”突变至关重要。最近开发的RNA-Seq方法为检测融合转录本提供了强大的工具。只需简单的样品制备，就能以低成本从下一代DNA测序仪中收集大量短cDNA序列。大量的序列为全面鉴定融合转录本及其原始基因组畸变提供了丰富的资源。 在本提案中，我们计划对 AML（急性髓系白血病）（白血病的一种主要类型）中的融合转录本及其染色体结构畸变进行系统分析。尽管在 AML 中已发现一致的染色体结构变化，但一半的 AML 病例不包含那些已知的染色体结构畸变。这些 AML 病例的临床结果与已知易位的病例不同，表明正常核型 AML 可能包含不同的遗传畸变。在本提案中，我们计划使用RNA-Seq方法从50个AML样本中获得全面的转录组。我们计划进行广泛的信息学分析，以识别融合转录本和其他变化，以便定位其在疾病基因组中的原始结构畸变。 该研究的潜在影响将是提供AML融合和遗传畸变的全面图谱，鉴定参与AML的新候选基因，为识别“驱动”突变提供新的候选基因，为癌症亚型分类和更好地诊断、治疗和预后AML提供新的遗传标记。 公共健康相关性：该提案计划对急性髓系白血病的融合转录本进行全面检测，旨在识别导致该疾病的新基因，并确定用于该疾病临床诊断、治疗和预后的新标志物。