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Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.

Publication ,  Journal Article
Marcucci, G; Metzeler, KH; Schwind, S; Becker, H; Maharry, K; Mrózek, K; Radmacher, MD; Kohlschmidt, J; Nicolet, D; Whitman, SP; Wu, Y-Z ...
Published in: J Clin Oncol
March 1, 2012

PURPOSE: 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). PATIENTS AND METHODS: 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. RESULTS: Younger (< 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. CONCLUSION: 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.

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

March 1, 2012

Volume

30

Issue

7

Start / End Page

742 / 750

Location

United States

Related Subject Headings

  • Young Adult
  • Prognosis
  • Oncology & Carcinogenesis
  • Mutation
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute
  • Humans
  • Gene Expression Profiling
  • Female
 

Citation

APA
Chicago
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MLA
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Marcucci, G., Metzeler, K. H., Schwind, S., Becker, H., Maharry, K., Mrózek, K., … Bloomfield, C. D. (2012). Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol, 30(7), 742–750. https://doi.org/10.1200/JCO.2011.39.2092
Marcucci, Guido, Klaus H. Metzeler, Sebastian Schwind, Heiko Becker, Kati Maharry, Krzysztof Mrózek, Michael D. Radmacher, et al. “Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.J Clin Oncol 30, no. 7 (March 1, 2012): 742–50. https://doi.org/10.1200/JCO.2011.39.2092.
Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrózek K, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012 Mar 1;30(7):742–50.
Marcucci, Guido, et al. “Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.J Clin Oncol, vol. 30, no. 7, Mar. 2012, pp. 742–50. Pubmed, doi:10.1200/JCO.2011.39.2092.
Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrózek K, Radmacher MD, Kohlschmidt J, Nicolet D, Whitman SP, Wu Y-Z, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Moore JO, Caligiuri MA, Larson RA, Bloomfield CD. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012 Mar 1;30(7):742–750.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

March 1, 2012

Volume

30

Issue

7

Start / End Page

742 / 750

Location

United States

Related Subject Headings

  • Young Adult
  • Prognosis
  • Oncology & Carcinogenesis
  • Mutation
  • Middle Aged
  • Male
  • Leukemia, Myeloid, Acute
  • Humans
  • Gene Expression Profiling
  • Female