Service d'Hématologie Clinique Adulte et de Thérapie Cellulaire, Centre Hospitalier Universitaire (CHU) de Clermont-Ferrand, Clermont-Ferrand, France; Equipe d'accueil (EA) 7283-Cancer Resistance Exploring and Targeting (CREAT), Centre d'Investigation Clinique (CIC) 501, Université d'Auvergne, Clermont-Ferrand, France;
Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
Blood. 2015 Oct 29;126(18):2110-7. doi: 10.1182/blood-2015-05-647578. Epub 2015 Aug 27.
Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ≥ 2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥ 2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome.
虽然 TP53、NOTCH1 和 SF3B1 突变可能会影响接受一线治疗的慢性淋巴细胞白血病 (CLL) 患者的预后，但这些突变或任何其他突变单独或联合的影响在复发时仍不清楚。前瞻性试验中纳入的 114 例复发/难治性患者的基因组使用针对 TP53、SF3B1、ATM、NOTCH1、XPO1、SAMHD1、MED12、BIRC3 和 MYD88 基因的靶向下一代测序进行了筛选。我们根据反复出现的基因突变的数量和组合进行了聚类。43 名（38%）、49 名（43%）和 22 名（19%）患者分别有≥2、1 和 0 个基因受到突变影响。在 22 名（19%）患者中发现了≥2 个 TP53、SF3B1 和 ATM 基因突变的反复组合。与其余患者的 22.5 个月相比，这种多次打击的特征与中位无进展生存期为 12 个月相关（P=0.003）。复发/难治性 CLL 患者中经常发生同时存在的基因突变，并且与预后较差相关。
