Age-Related Prognostic Impact of Different Types of DNMT3A Mutations in Adults With Primary Cytogenetically Normal Acute Myeloid Leukemia
Age-Related Prognostic Impact of Different Types of DNMT3A Mutations in Adults With Primary Cytogenetically Normal Acute Myeloid Leukemia
复制标题
DOI：
10.1200/jco.2011.39.2092
复制
发表时间：
2012-03-01
影响因子：
45.3
通讯作者：
Bloomfield, Clara D.
中科院分区：
文献类型：
--
作者：
Marcucci, Guido;Metzeler, Klaus H.;Bloomfield, Clara D.
目的探讨DNMT3A突变在细胞遗传学正常的急性髓系白血病(CN-AML)患者中的频率及其与临床、分子特征和预后的关系，以及相关基因和microRNA的表达特征。结果青年组(60岁；n=181)和老年组(>；=60岁；n=234)DNMT3A基因突变频率相似(35.3%比33.3%)。影响精氨酸密码子882(R882-DNMT3A)的错义突变比影响其他密码子(非R882-DNMT3A)的错义突变更常见(n=92；62%)。DNMT3A突变患者在完全缓解率方面没有差异，但无病生存期(DFS；P=0.03)和总生存期(OS；P=0.07)都比DNMT3A野生型患者短。在多变量分析中，DNMT3A突变仍然与较短的DFS相关(P=0.01)，但与较短的OS无关。单独分析时，两种DNMT3A突变类型在不同年龄组具有不同的意义。在调整了其他临床和分子预测因素后，非R882-DNMT3A突变的年轻患者的DFS(P=.002)和OS(P=.02)较短，而R882-DNMT3A突变的老年患者的DFS(P=.005)和OS(P=.002)较短。基因和microRNA表达特征不能准确预测DNMT3A突变状态。结论DNMT3A突变在CN-AML中常见，其临床意义似乎与年龄有关。DNMT3A-R882突变与老年患者预后不良相关，非R882-DNMT3A突变与年轻患者预后不良相关。基因和microRNA表达特征预测DNMT3A突变状态的准确性较低，这表明这些突变在AML中的作用仍有待阐明。
PurposeTo determine the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene-and microRNA-expression signatures in primary cytogenetically normal acute myeloid leukemia (CN-AML).Patients and MethodsFour hundred fifteen previously untreated adults were analyzed for DNMT3A mutations and established prognostic gene mutations and expression markers. Gene-and microRNA-expression profiles were derived using microarrays.ResultsYounger (< 60 years; n = 181) and older (>= 60 years; n = 234) patients had similar frequencies of DNMT3A mutations (35.3% v 33.3%). Missense mutations affecting arginine codon 882 (R882-DNMT3A) were more common (n = 92; 62%) than those affecting other codons (non-R882-DNMT3A). DNMT3A-mutated patients did not differ regarding complete remission rate, but had shorter disease-free survival (DFS; P = .03) and, by trend, overall survival (OS; P = .07) than DNMT3A-wild-type patients. In multivariable analyses, DNMT3A mutations remained associated with shorter DFS (P = .01), but not with shorter OS. When analyzed separately, the two DNMT3A mutation types had different significance by age group. Younger patients with non-R882-DNMT3A mutations had shorter DFS (P = .002) and OS (P = .02), whereas older patients with R882-DNMT3A mutations had shorter DFS (P = .005) and OS (P = .002) after adjustment for other clinical and molecular prognosticators. Gene-and microRNA-expression signatures did not accurately predict DNMT3A mutational status.ConclusionDNMT3A mutations are frequent in CN-AML, and their clinical significance seems to be age dependent. DNMT3A-R882 mutations are associated with adverse prognosis in older patients, and non-R882-DNMT3A mutations are associated with adverse prognosis in younger patients. Low accuracy of gene-and microRNA-expression signatures in predicting DNMT3A mutation status suggested that the role of these mutations in AML remains to be elucidated.