Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia
Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia
复制标题
DOI：
10.1200/jco.2014.59.2022
复制
发表时间：
2015-06-20
影响因子：
45.3
通讯作者：
Linch, David C.
中科院分区：
文献类型：
--
作者：
Gale, Rosemary E.;Lamb, Katarina;Linch, David C.
PurposeTo evaluate the impact of DNMT3A mutations on outcome in young patients with cytogenetically intermediate-risk acute myeloid leukemia.Patients and MethodsDiagnostic samples from 914 patients（97% < 60 years old）were screened for mutations in DNMT3A exon 13 to 23.根据突变的存在与否评估临床结果，并根据突变类型（R882、非R882错义或截短）进行分层。结果在272例（30%）患者中发现DNMT 3A突变（DNMT 3A（MUT）），与野生型DNMT 3A相比，其预后较差，但仅在根据NPM 1基因型分层时观察到差异。这个辛普森悖论的例子是由于DNMT 3A和NPM 1突变的高度一致性（80%的DNMT 3A（MUT）患者有NPM 1突变），其中两种突变具有相反的预后影响。在分层分析中，DNMT 3A（MUT）患者的复发率较高（风险比，1.35; 95%CI，1.07至1.72; P = .01），总生存率较低（风险比，1.37; 95%CI，1.12至1.87; P = .002）。根据NPM 1基因型，DNMT 3A（MUT）的影响没有差异（异质性检验：复发，P = .4;总生存期，P = .9）。根据DNMT 3A突变类型的进一步分析表明，在R882和非R882错义突变的患者中，结果是相当的，而在那些截短突变的患者中，它与野生型DNMT 3A相当。结论这些数据证实，DNMT 3A突变的存在应被认为是一个不良的风险预后因素，无论NPM 1基因型如何，提示应进一步考虑DNMT 3A突变的类型。(C)2015年美国临床肿瘤学会
PurposeTo evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.Patients and MethodsDiagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation).ResultsDNMT3A mutations (DNMT3A(MUT)) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3A(MUT) had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3A(MUT) was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3A(MUT) did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A.ConclusionThese data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation. (C) 2015 by American Society of Clinical Oncology