PURPOSE Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. EXPERIMENTAL DESIGN We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. RESULTS Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. CONCLUSIONS We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

中文翻译：

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在慢性淋巴细胞性白血病中，因驾驶员突变而改变的信号通路数量影响了疾病结果。

目的在新诊断的慢性淋巴细胞性白血病（CLL）患者的连续队列中研究由复发性基因突变改变的信号通路及其临床影响。CLL的异质临床过程和遗传复杂性可确保改善分子预后。然而，在诊断时复发突变的预后价值仍不清楚。实验设计我们对来自314位连续，新诊断的CLL患者的样品进行了测序，以研究通过下一代测序评估的56个重复突变基因的临床影响。结果IGHV未突变病例中有70％的富集患者发现了突变。经过6.5年的随访，诊断时研究的15个突变基因显示出对首次治疗时间（TTFT）的显着影响。携带驾驶员突变与较短的TTFT和较差的总体存活率有关。对于CLL诊断的结果，由驱动程序突变改变的信号通路数量使患者分层的效果优于驱动程序突变的数量。此外，我们证明了随着TCL途径的逐渐改变，途径的改变与CLL-IPI风险无关。因此，评估复发突变的基于25基因，基于途径的生物标记物可改善CLL的预后，特别是对于CLL-IPI低危和中危患者。外部验证强调，包括低负荷突变在内的广泛基因组是基于改变途径的生物标志物的关键。