p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)
p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)
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DOI：
10.3324/haematol.2013.098103
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发表时间：
2014-06-01
期刊：
影响因子：
10.1
通讯作者：
Hellstrom-Lindberg, Eva
中科院分区：
文献类型：
--
作者：
Saft, Leonie;Karimi, Mohsen;Hellstrom-Lindberg, Eva
Del(5q) 骨髓增生异常综合征被国际预后评分系统定义为低风险或中风险 1（低风险），被认为具有惰性病程；然而，最近的数据发现这些患者中的一个亚组患有更严重的疾病和更差的结果。我们之前使用深度测序技术证明，18% 的低风险 del(5q) 骨髓增生异常综合征患者携带 TP53 突变亚克隆，使他们面临更高的进展风险。在这项研究中，通过免疫组织化学回顾性评估了 MDS-004 临床试验中 85 名接受来那度胺治疗的患者的骨髓活检中 p53 的表达与结果的关系。在 35%（85 名患者中的 30 名）中观察到，>= 1% 的骨髓祖细胞中 p53 强表达与较高的急性髓性白血病风险（P=0.0006）、较短的总生存期（P=0.0175）和较低的细胞遗传学反应率（P=0.009）显着相关，但与 26 周输血独立反应的实现或持续时间无关。在多变量分析中，p53 阳性免疫组织化学是转化为急性髓系白血病的最强独立预测因子 (P=0.0035)。对具有强 p53 表达的激光显微切割细胞进行焦磷酸测序分析证实了 TP53 突变，而中等表达的细胞主要具有野生型 p53。这项研究验证了 p53 免疫组织化学对于低风险 del(5q) 骨髓增生异常综合征患者来说是一种强大且临床上有用的预测工具。本研究基于 MDS 004 试验的数据（clinicaltrials.gov 标识符：NCT00179621）。
Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in >= 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621).