Biomarkers of Disease Progression in CLL

描述(申请人提供)：我们已经组建了一个在临床研究、基因组学和生物信息学/生物统计学方面具有很高成就的多学科团队，目标是识别预后生物标志物，以更好地预测和了解慢性淋巴细胞白血病(CLL)的进展。CLL的病程多种多样，其发病机制尚不清楚：一些患者在病情进展之前有长期的惰性疾病，而另一些患者病情进展迅速，需要在诊断后相对较短的时间内进行治疗。虽然现有的生物标记物和临床因素可以将患者分为高风险组和低风险组，但仍然需要纵向生物标记物来指示在可变的惰性时期后进行性疾病的发展。我们有大量临床注释良好的CLL组织样本，并对结果进行长期跟踪，可从CLL临床研究联盟(CRC)的UCSD网站获得。样本包括可见的冷冻白血病细胞、白血病细胞DNA、RNA和生殖系DNA。我们提出了一项回顾性配对的病例对照研究，比较早期进展的CLL患者组(n=12)、晚期进展组(n=12)和长期惰性组(n=12)。进展较晚的组和长期惰性组分别在性别和进展时间或最后随访时间上进行匹配。这三组患者都在头两年内抽血两次；进展较晚和长期无进展的患者在确诊后3至8年内也有匹配的第三次抽血。我们将使用第二代测序来生成这96个CLL肿瘤样本的转录组数据(12个早期进展，在2个时间点采样；24个晚期进展和长期惰性，在3个时间点采样)。我们将量化基因和选择性剪接异构体的mRNA转录水平，并识别反复发生的突变。我们将使用这些数据在基线上识别候选生物标记物，然后通过发现早期进展组和其他两组在前两年变化分数上的差异来识别候选纵向生物标记物。三年后，我们将通过评估这些候选纵向生物标记物在晚期进展组和长期惰性组之间的显著差异来验证它们。最后，我们将把假定的纵向生物标记物与临床数据库中现有的已知预后因素结合起来。如果成功，我们的候选生物标记物将做好准备，在完整的CRC生物信息库中进行进一步验证，并建议进行前瞻性的临床研究。 公共卫生相关性：项目叙述慢性淋巴细胞白血病(CLL)是美国最常见的成人白血病。在这里，我们寻求通过开发生物标记物来更好地预测和了解疾病进展来改善CLL患者的医疗保健。

DESCRIPTION (provided by applicant): We have assembled a multidisciplinary team which is highly accomplished in clinical research, genomics, and bioinformatics/biostatistics, with the goal to identify prognostic biomarkers to better predict and understand progression of chronic lymphocytic leukemia (CLL). The course of CLL is variable and its pathogenesis is poorly understood: while some patients have long-term indolent disease prior to progression, others progress rapidly requiring therapy within a relatively short time after diagnosis. Although existing biomarkers and clinical factors can stratify patients into high and low risk groups, there remains a need for longitudinal biomarkers which can signal development of progressive disease after a variable indolent period. We have a large number of clinically well-annotated CLL tissue samples with long term follow-up on outcome, available from the UCSD site of the CLL Clinical Research Consortium (CRC). Samples include viably-frozen leukemia cells, leukemia-cell DNA, RNA, and germline DNA. We propose a retrospective matched case-control study comparing an early-progressing group of CLL patients (n=12) with a later-progressing (n=12) and a long-term indolent group (n=12). The later-progressing and long-term indolent groups are individually matched on gender and time to progression or time to last follow-up, respectively. All three groups have two blood draws within the first two years; the later-progressing and long-term progression-free patients also have a matched third blood draw between 3 and 8 years after diagnosis. We will use second-generation sequencing to generate transcriptome data for these 96 CLL tumor samples (12 early-progressing, sampled at 2 time points; 24 later-progressing and long-term indolent, sampled at 3 time points). We will quantify mRNA transcript levels for genes and for alternative splice isoforms, and identify recurrent mutations. We will use these data to identify candidate biomarkers at baseline, and then identify candidate longitudinal biomarkers by finding differences between early-progressing and the other two groups in the change score during the first two years. We will validate these candidate longitudinal biomarkers by assessing them for significant differences between later progressing and long-term indolent groups after three years. Finally, we will integrate putative longitudinal biomarkers with existing known prognostic factors in the clinical database. If successful, our candidate biomarkers will be well poised to carry forward for further validation in the full CRC biorepository, and to propose for prospective clinical studies. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the United States. Here we seek to improve the health care of CLL patients by developing biomarkers to better predict and understand disease progression.