Ok Chi Young, Patel Keyur P, Garcia-Manero Guillermo, Routbort Mark J, Peng Jie, Tang Guilin, Goswami Maitrayee, Young Ken H, Singh Rajesh, Medeiros L Jeffrey, Kantarjian Hagop M, Luthra Rajyalakshmi, Wang Sa A
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA.
J Hematol Oncol. 2015 May 8;8:45. doi: 10.1186/s13045-015-0139-z.
TP53 mutation is more prevalent in therapy-related myeloid neoplasms (t-MN) than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown.
We collected 108 consecutive patients with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML). Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS/AML was included for comparison.
We assessed 108 patients with t-MN, in which 40 patients (37%) had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS/AML (62/428 patients, 14.5%) (p<0.0001). TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% (range, 7.1 to 98.8). Most mutations involved single nucleotide changes, of which, transitions (65.9%) were more common than transversions (34.1%). Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS/AML. TP53 mutations in t-MN were associated with a complex karyotype (p<0.0001), a higher number of chromosomal abnormalities (p<0.0001), and an inferior overall survival in affected patients (6.1 vs 14.1 months) by univariate (p<0.0001) and multivariate analyses (p=0.0020).
Our findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors.
与初发的骨髓肿瘤相比，TP53突变在治疗相关的髓系肿瘤（t-MN）中更为普遍；然而，t-MN与初发疾病中涉及TP53基因的突变模式在很大程度上尚不清楚。
我们收集了108例连续的治疗相关骨髓增生异常综合征（t-MDS）/急性髓系白血病（t-AML）患者。通过检索电子病历收集临床、血液学和细胞遗传学数据。使用经过临床验证的基于二代测序的基因检测板对所有患者进行TP53测序。纳入一个先前发表的由428例初发MDS/AML患者组成的队列进行比较。
我们评估了108例t-MN患者，其中40例（37%）有TP53突变。t-MDS和t-AML之间的突变频率相似；但显著高于初发MDS/AML（62/428例患者，14.5%）（p<0.0001）。t-MN中的TP53突变主要聚集在DNA结合域，等位基因频率为37.0%（范围为7.1%至98.8%）。大多数突变涉及单核苷酸变化其中转换（65.9%）比颠换（34.1%）更常见。错义突变最常见，其次是移码突变和无义突变。这种TP53突变模式与在初发MDS/AML中观察到的模式惊人地相似。t-MN中的TP53突变与复杂核型（p<0.0001）、更多的染色体异常（p<0.0001）以及受影响患者较差的总生存期（6.1个月对14.1个月）相关，单因素分析（p<0.0001）和多因素分析（p=0.0020）均如此。
我们的研究结果支持最近的观点，即杂合性TP53突变可能是正常衰老的一种表现，并且突变细胞在接触细胞毒性治疗后会受到选择。携带TP53突变的t-MN具有侵袭性的临床病程，独立于其他混杂因素。
