Division of Computational Biology, Mayo Clinic, Rochester, MN.
Department of Hematology/Oncology, Mayo Clinic, Phoenix, AZ.
Blood Adv. 2023 Jul 11;7(13):3169-3179. doi: 10.1182/bloodadvances.2022009040.
TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.
TP53 异常，包括 17p13 的突变和缺失，是慢性淋巴细胞白血病（CLL）的重要不良预后标志物，但在高计数单克隆 B 细胞淋巴增生症（HCMBL）中研究较少，HCMBL 是 CLL 的无症状前恶性阶段。在这里，我们评估了 1230 例新诊断的未经治疗的初治个体（849 例 CLL，381 例 HCMBL）中 TP53 异常的患病率和影响。我们将 TP53 状态定义为：野生型（无 TP53 突变和 17p 正常）、单次打击（del(17p)或一个 TP53 突变）或多次打击（TP53 突变和 del(17p)，TP53 突变和杂合性丢失，或多个 TP53 突变）。使用 Cox 回归估计按 TP53 状态划分的首次治疗时间和总生存时间的风险比（HR）和 95%置信区间（CI）。我们发现 64 例（7.5%）CLL 患者和 17 例（4.5%）HCMBL 个体的 TP53 突变的等位基因变异分数>10%。58 例（6.8%）CLL 和 11 例（2.9%）HCMBL 病例中存在 del(17p)。大多数个体的 TP53 状态为野生型（N=1,128，91.7%），其次是多打击（N=55，4.5%），然后是单打击（N=47，3.8%）。TP53 异常的数量越多，治疗时间和死亡的风险就越高。与野生型患者相比，多打击患者需要治疗的风险增加了 3 倍，单打击患者增加了 1.5 倍。与野生型相比，多打击患者的死亡风险也增加了 2.9 倍。在考虑其他已知不良预后因素后，这些结果仍然稳定。TP53 突变和 del(17p)都可能为 HCMBL 和 CLL 提供重要的预后信息，如果只测量一个，则可能会遗漏这些信息。
