Biomarkers of Disease Progression in CLL

描述（由申请人提供）：我们组建了一个多学科团队，在临床研究，基因组学和生物信息学/生物统计学方面取得了很高的成就，目标是确定预后生物标志物，以更好地预测和了解慢性淋巴细胞白血病（CLL）的进展。CLL的病程是可变的，其发病机制知之甚少：虽然一些患者在进展前患有长期惰性疾病，但其他患者在诊断后相对较短的时间内迅速进展需要治疗。尽管现有的生物标志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志物，其可以在可变的惰性期后发出进展性疾病的发展的信号。 我们拥有大量临床注释良好的CLL组织样本，并对结果进行长期随访，可从CLL临床研究联盟（CRC）的加州大学圣地亚哥分校网站获得。样本包括可存活的冷冻白血病细胞、白血病细胞DNA、RNA和生殖系DNA。我们提出了一项回顾性配对病例对照研究，比较早期进展组CLL患者（n = 12）与晚期进展组（n=12）和长期惰性组（n=12）。晚期进展组和长期惰性组分别在性别和至进展时间或至末次随访时间上单独匹配。所有三组在前两年内都有两次抽血;晚期进展和长期无进展患者在诊断后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）。我们将定量mRNA转录水平的基因和选择性剪接异构体，并确定复发性突变。我们将使用这些数据来确定基线时的候选生物标志物，然后通过发现早期进展组和其他两组在前两年的变化评分中的差异来确定候选纵向生物标志物。我们将通过评估这些候选纵向生物标志物在三年后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，我们将整合假定的纵向生物标志物与临床数据库中现有的已知预后因素。如果成功，我们的候选生物标志物将在完整的CRC生物储存库中进行进一步验证，并提出前瞻性临床研究。 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志物来更好地预测和了解疾病进展，从而改善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.