Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, UK.
Nat Commun. 2021 Jan 28;12(1):665. doi: 10.1038/s41467-020-20822-9.
Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.
由于慢性淋巴细胞白血病（CLL）临床过程的异质性，其预后预测具有挑战性。我们假设体质遗传变异会影响疾病进展，并有助于预后预测。汇集了来自 7 项研究的数据，共纳入 842 例病例，确定了与从诊断到治疗的时间相关的两个基因组位置，包括 10q26.13（rs736456，风险比（HR）= 1.78，95%置信区间（CI）= 1.47-2.15；P=2.71×10）和 6p（rs3778076，HR=1.99，95%CI=1.55-2.55；P=5.08×10），这些位置在其他特征为低风险的早期 CLL 患者中是特别强大的预后标志物。表达数量性状基因座分析确定了可能影响 B 细胞受体或先天免疫反应的功能基因，这些基因是 CLL 发病机制中的关键途径。在这项工作中，我们确定了 rs736456 和 rs3778076 与 CLL 的预后相关，表明疾病进展是由体质遗传变异以及已知的体细胞驱动因素决定的。
