Genetic Biomarkers for Risk of CLL Progression among high-count MBLs

单克隆B细胞淋巴细胞增多症（MBL）是慢性淋巴细胞白血病（CLL）的前体状态， 最常见的癌前病变MBL存在于5%-10%的40岁以上的成年人群中 (6-12百万美国成年人），是一种无症状的条件，其特征是绝对B细胞计数 <5x 109/L，无淋巴组织增生性疾病的其他特征。这种情况被细分为低计数 MBL和高计数（HC）MBL取决于绝对B细胞计数是否高于或低于0.5x109/L。 HC MBL个体以1-5%/年的速率发展为需要治疗的CLL。因为， 进展风险，临床实践指南建议每年随访HC MBL，以获得 疾病进展（即，观察和等待策略）。虽然这些人在技术上没有 白血病，这种观察和等待的策略会导致焦虑和痛苦。因此，有一个重要的需要， 确定推动HC-MBL患者进展的因素。在本申请中，我们提出 满足这一需求。有一些证据表明，与疾病进展风险相关的生物标志物 在CLL中，也与HC MBL的进展风险相关，包括β2-微球蛋白和未突变的 免疫球蛋白重链（IGHV）。此外，现有的全基因组测序和全外显子组测序技术， 测序研究已经在CLL患者中鉴定了约60个具有复发性体细胞变异的基因。许多这些 CLL反复突变的基因也被发现在患有HC MBL的个体中发生突变，特别是， 发现TP 53、NOTCH 1和SF 3B 1的突变与从HC MBL进展为CLL相关。 在初步数据中，我们发现复发突变的CLL基因的总数[即，肿瘤突变 负荷（TML）]是新诊断的HC MBL个体中CLL进展的预后指标。在目标1中，我们提出 通过在一个更大的HC-MBL队列中评估TML伴CLL进展来扩展这些激发性发现 个体除了体细胞突变，我们和其他人已经确定了41个遗传性单核苷酸 通过全基因组关联研究，来自35个基因座的多态性（SNP）与CLL风险相关。 我们计算了多基因风险评分（PRS），这是这些SNP的风险等位基因的加权平均值， 发现PRS是CLL和MBL的强危险因素。在初步数据中我们发现 这种PRS可能与CLL的进展有关。在目标2中，我们建议进一步评估PRS 在HC MBL个体中CLL进展。从该应用程序中获得的知识将提供 MBL进展为需要治疗的CLL的新生物标志物。这些结果可能会改变目前的做法 指导方针，反过来，通过减少这些人的焦虑和痛苦来提高生活质量。随着新 CLL的有效靶向治疗出现后，考虑早期干预的兴趣重新燃起。 问题研究TML和PRS可能是识别HC MBL患者的两个潜在生物标志物， 可能会从这种早期干预中受益。

Monoclonal B-cell lymphocytosis (MBL) is a precursor state to chronic lymphocytic leukemia (CLL), and one of the most common premalignant conditions. MBL is present in 5-10% of the adult population over age 40 years (6-12 million U.S. adults) and is an asymptomatic condition that is characterized by an absolute B-cell count <5x109/L and no other features of a lymphoproliferative disorder. This condition is subdivided into low-count MBL and high-count (HC) MBL depending on whether the absolute B-cell count is above or below 0.5x109/L. HC MBL individuals progress to develop CLL requiring therapy at a rate of 1-5%/year. Because of the elevated progression risk, clinical practice guidelines recommend that HC MBLs be followed annually for evidence of disease progression (i.e., watch and wait strategy). Although these individuals technically do not have leukemia, this watch and wait strategy causes anxiety and distress. Thus, there is an important need in identifying factors that drive progression among individuals with HC-MBL. In this application we propose to address this need. There is some evidence that biological markers associated with risk of progressive disease in CLL are also associated with risk of progression in HC MBL, including β2-microglobulin and unmutated immunoglobulin heavy chain (IGHV). Moreover, prior whole genome sequencing and whole exome sequencing studies have identified ~60 genes with recurrent somatic variants in CLL patients. Many of these CLL recurrently mutated genes were also found to be mutated in individuals with HC MBL, and in particular, mutations in TP53, NOTCH1, and SF3B1 were found to be associated with progression from HC MBL to CLL. In preliminary data, we found that the total number of recurrently mutated CLL genes [i.e., tumor mutational load (TML)] was prognostic for CLL progression in newly diagnosed HC MBL individuals. In Aim 1 we propose to extent these provocative findings by evaluating the TML with CLL progression in a larger cohort of HC-MBL individuals. In addition to somatic mutations, we and others have identified 41 inherited single nucleotide polymorphisms (SNPs) from 35 loci to be associated with CLL risk through genome-wide association studies. We computed a polygenic risk score (PRS), which is a weighted average of the risk alleles across these SNPs, and found that the PRS is a strong risk factor for both CLL and MBL. In preliminary data we found evidence that this PRS may be associated with progression in CLL. In Aim 2 we propose to further evaluate the PRS with CLL progression among HC MBL individuals. The knowledge gained from this application will provide novel biomarkers for MBL progression to CLL requiring therapy. These results may change current practice guidelines, and in turn, improve quality of life by reducing anxiety and distress for these individuals. As new effective targeted therapies emerge for CLL, there is renewed interest in consideration of early intervention studies. The TML and PRS may be two potential biomarkers for identifying HC MBL individuals who most likely to benefit from such early intervention.