Age-Related Prognostic Impact of Different Types of DNMT3A Mutations in Adults With Primary Cytogenetically Normal Acute Myeloid Leukemia

作者：Marcucci Guido^*; Metzeler Klaus H; Schwind Sebastian; Becker Heiko; Maharry Kati; Mrozek Krzysztof; Radmacher Michael D; Kohlschmidt Jessica; Nicolet Deedra; Whitman Susan P; Wu Yue Zhong; Powell Bayard L; Carter Thomas H; Kolitz Jonathan E; Wetzler Meir; Carroll Andrew J; Baer Maria R; Moore Joseph O; Caligiuri Michael A; Larson Richard A; Bloomfield Clara D

来源：Journal of Clinical Oncology, 2012, 30(7): 742-750.

DOI：10.1200/JCO.2011.39.2092

Purpose %26lt;br%26gt;To 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). %26lt;br%26gt;Patients and Methods %26lt;br%26gt;Four 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. %26lt;br%26gt;Results %26lt;br%26gt;Younger (%26lt; 60 years; n = 181) and older (%26gt;= 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. %26lt;br%26gt;Conclusion %26lt;br%26gt;DNMT3A 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.

• 出版日期2012-3-1