GENOMIC ANALYSIS OF ADOLESCENT AND YOUNG ADULT ACUTE LYMPHOBLASTIC LEUKEMIA

描述(由申请者提供)：挑战领域：15：翻译科学 挑战主题：15-CA-105：青少年癌症生物学。 项目名称：青春期急性淋巴细胞白血病的基因组分析 急性淋巴细胞性白血病(ALL)是青少年和青壮年(Aya)人群癌症相关死亡的主要原因之一。与年龄较小的ALL儿童相比，Aya ALL的总体结果明显较差。这些结果的差异是由于不同的潜在遗传和生物学特征还是不同的治疗方法仍有待确定。迫切需要研究Aya ALL的潜在生物学和遗传学基础，并与已被广泛研究的年幼儿童和老年人进行比较，以(1)确定不同年龄组与ALL相关的不同基因变化的频谱和变异及其预后重要性，以及(2)确定新的治疗靶点。我们最近对标准和高危儿童ALL进行了详细的基因组特征分析，使用了互补基因表达谱、全基因组遗传改变分析和靶向基因重测序。通过这些努力，我们已经确定了多种新的基因组改变，这些改变扰乱了关键的细胞通路，并与治疗结果的显着差异有关。重要的是，候选基因重新测序也在高危儿童中发现了新的激酶突变，所有这些都代表了新的治疗目标。在我们对1000多名儿童的研究中，我们研究了50多名年龄较小的Aya谱患者(16-21岁)。有趣的是，这些Aya ALL病例似乎具有在儿童ALL高危类型中更常见的潜在遗传和生物学特征，包括淋巴转录因子IKAROS的基因改变，JAK激酶的突变，以及与极其糟糕的预后相关的基因表达特征。这些发现表明，对一大批Aya ALL患者进行相对详细的基因组分析，可能会对这一独特群体患者的不良结局产生关键的见解，并可能确定新的治疗靶点。这项研究将在一大批Aya ALL病例中进行互补基因表达谱分析、DNA拷贝数改变的全基因组分析和候选基因重测序。将使用现有的Aya ALL样本和来自NCI合作肿瘤学小组的相关临床、表型和结果数据对400例Aya ALL患者进行研究。这将使首次对Aya All进行完整的基因组分析成为可能。这些辅助方法将允许：(1)鉴定Aya ALL中反复出现的DNA拷贝数改变，以及与对局部和全球基因表达模式的影响的相关性；(2)鉴定与结果相关的基因表达特征；(3)基因组数据的路径分析，以确定基因组改变所涉及的细胞通路；以及(4)鉴定Aya ALL中已知突变的基因的序列突变，以及Aya ALL队列中基因组改变的新靶点。原则调查员在实施这些方法和分析所有大型数据集的结果数据方面拥有丰富的经验。通过NCI在高危儿科ALL中的联合目标项目，他们在过去两年中进行了广泛的合作并联合发表了论文。重要的是，该项目产生的所有数据将通过NCI癌症基因组工作台公开，以促进结果的公开传播。该项目将为更好地描述Aya ALL的生物学特征和确定治疗失败的原因提供宝贵的机会。最终，这些数据将为研究这种疾病的新治疗方法奠定基础。 公共卫生相关性：急性淋巴细胞性白血病(ALL)是青少年(AYA)癌症相关死亡的主要原因。与目前存活率超过80%的ALL儿童相比，Aya ALL的治疗结果很差。为什么Aya ALL的结果比儿童更糟糕，人们对此知之甚少。我们之前已经使用详细的基因组图谱检查了大量儿童ALL肿瘤样本的遗传特征，并确定了预测预后的新的基因改变，也确定了新的治疗靶点。我们现在希望在Aya All中进行类似的分析，目的是提高我们对疾病生物学的理解，对治疗结果的遗传决定因素的理解，确定新的治疗目标，并最终改善结果。这项研究提供了在阿亚死亡的主要原因之一方面提供重要见解和进展的机会。

DESCRIPTION (provided by applicant): Challenge Area: 15: Translational Science Challenge Topic: 15-CA-105: The Biology of Cancer in Adolescents and Young Adults. Project title: Genomic Analysis of Adolescent and Young Adult Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is one of the leading causes of cancer related death in the adolescent and young adult (AYA) population. Relative to younger children with ALL, the overall outcomes in AYA ALL are significantly poorer. Whether these outcome differences are due to distinct underlying genetic and biologic features or different therapeutic approaches remain to be determined. Studies examining the underlying biologic and genetic basis of AYA ALL, and comparison to younger children who have been extensively studied and older adults, are urgently required to (1) determine the spectrum and variation of distinct ALL-associated genetic alterations in different age groups and their prognostic importance, and (2) to identify novel therapeutic targets. We have recently performed detailed genomic characterization of standard and high risk pediatric ALL using complementary gene expression profiling, genome-wide analysis of genetic alterations, and targeted gene resequencing. Through these efforts we have identified multiple novel genomic alterations that perturb key cellular pathways and which are associated with significant differences in the outcome of therapy. Importantly, candidate gene resequencing has also identified novel kinase mutations in children with high risk ALL that represent novel targets for therapy. In our studies of over 1000 children, we have studied over 50 patients at the younger age end of the AYA spectrum (age 16-21). Interestingly these AYA ALL cases appear to have underlying genetic and biologic features more commonly seen in higher risk forms of pediatric ALL, including genetic alteration of the lymphoid transcription factor IKAROS, mutation of JAK kinases, and a gene expression signature associated with an extremely poor outcome. These findings suggest that a comparably detailed genomic analysis of a large cohort of AYA ALL patients is likely to yield critical insights into the poor outcome of this unique group patients, and also may identify novel therapeutic targets. This study will perform complementary gene expression profiling, genome-wide analysis of DNA copy number alterations, and candidate gene resequencing in a large cohort of AYA ALL cases. Four hundred cases spanning the age range of AYA ALL will be studied, using existing AYA ALL samples with associated clinical, phenotypic and outcome data from the NCI Cooperative Oncology Groups. This will enable the first integrated genomic analysis of AYA ALL. The complementary approaches will permit: (1) identification of recurring DNA copy number alterations in AYA ALL, and correlation with effects on local and global gene expression patterns; (2) identification of gene expression signatures that correlate with outcome; (3) pathway analysis of genomic data to identify cellular pathways involved by genomic alterations; and (4) identification of sequence mutations in genes known to be mutated in pediatric ALL, and also in novel targets of genomic alteration in the AYA ALL cohort. The principle investigators have extensive experience in the implementation of these approaches and analysis of the resulting data in large ALL datasets. Through a joint NCI TARGET project in high risk pediatric ALL, they have collaborated extensively and jointly published over the past two years. Importantly, all data resulting from this project will be made publicly available through The NCI Cancer Genome Workbench to facilitate public dissemination of the results. This project will provide an invaluable opportunity to better characterize the biology of AYA ALL and determine the reasons for treatment failure. Ultimately, these data will for the foundation for studies characterizing novel therapeutic approaches in this disease. PUBLIC HEALTH RELEVANCE: Acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in adolescents and young adults (AYA). In contrast to children with ALL, for whom survival rates now exceed 80%, the outcome of treatment in AYA ALL is poor. The reasons why the outcome of AYA ALL is worse than in children are poorly understood. We have previously examined the genetic features in large numbers of childhood ALL tumor samples using detailed genomic profiling, and have identified new genetic alterations that predict prognosis, and have also identified new targets for treatment. We now wish to perform similar analyses in AYA ALL, with the aims of improving our understanding the biology of the disease, our understanding of the genetic determinants of treatment outcome, indentifying new treatment targets, and ultimately improving outcome. This study offers the opportunity to provide important insights and advances in one of the leading causes of AYA death.