Abstract
Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes
Blood, Vol.116(21), pp.99-99
11/19/2010
DOI: 10.1182/blood.V116.21.99.99
Abstract
Abstract
Abstract 99
Whole genome sequencing with next generation technologies represents a new, unbiased approach for discovering somatic variations in cancer genomes. Our group recently reported the DNA sequence and analysis of the genomes of two patients with normal karyotype acute myeloid leukemia (AML). Improvements in next generation sequencing technologies (principally, paired-end sequencing) led us to reevaluate the first case (Ley et al, Nature 456:66–72, 2008) with deeper sequence coverage. We discovered a novel frameshift mutation in DNMT3A, one of the three genes in humans (DNMT1, DNMT3A, and DNMT3B) that encodes a DNA methyltransferase that catalyzes the addition of methyl groups to cytosine within CpG dinucleotides. We then sequenced all the coding exons of this gene in 280 additional de novo cases of AML to define recurring mutations. 62/281 de novo AML cases (22%) had mutations with translational effects in the DNMT3A gene. 18 different missense mutations were identified, the most common of which was at amino acid R882 (37 cases). Frameshifts (n=6), nonsense mutations (n=6), splice site mutations (n=3), and a 1.5 Mbp deletion that included the DNMT3A gene were also identified. DNMT3A mutations were highly enriched in cases with intermediate risk cytogenetics (56/166=33.7%; p<0.0001) and were not found in any cases with favorable cytogenetics (0/79; p<0.0001). Genomic 5-methylcytosine content, the general pattern of CpG island methylation, and gene expression patterns were essentially unaltered in genomes with DNMT3A mutations. The median overall survival of all AML patients with DNMT3A mutations was strikingly reduced, regardless of whether the mutation was at R882 or any other site (12.3 vs. 41.1 months, p<0.0001, Figure A). Patients with a FLT3 ITD mutation and no DNMT3A mutation (n=39) had a median survival of 33.5 months, but patients with a FLT3 ITD mutation and any DNMT3A mutation (n=18) had a median survival of 7.7 months (p=0.003, Figure B). Finally, DNMT3A mutation status independently predicted poor outcomes in a Cox Proportional Hazards analysis. In sum, DNMT3A mutations are highly recurrent in de novo AML cases with intermediate risk cytogenetics, and are independently associated with poor survival. These mutations may be valuable for identifying patients who need early intensification of therapy (allogeneic stem cell transplantation and/or innovative early phase clinical trials in first remission or consolidation).
Disclosures:
Westervelt: Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. DiPersio:Genzyme: Honoraria.
Details
- Title: Subtitle
- Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes
- Creators
- Timothy J Ley - Departments of Medicine & Genetics, The Genome Center, Siteman Cancer Center, Washington University, St. Louis, MO, USA,Li Ding - Washington University in St. LouisMatthew J. Walter - Washington University in St. LouisMichael D. McLellan - Washington University in St. LouisTamara Lamprecht - Washington University in St. LouisDavid E. Larson - The Genome Center, Washington University, St. Louis, MO, USACyriac Kandoth - Washington University in St. LouisJacqueline E. Payton - Washington University in St. LouisJack Baty - Washington University in St. LouisJohn S. Welch - Department of Medicine, Washington University, St. Louis, MO, USAChristopher C. Harris - The Genome Center, Washington University, St. Louis, MO, USACheryl F. Lichti - Washington University in St. LouisR. Reid Townsend - Washington University in St. LouisRobert S. Fulton - Washington University in St. LouisDavid J. Dooling - Washington University in St. LouisDaniel C. Koboldt - Washington University in St. LouisHeather Schmidt - Washington University in St. LouisQunyuan Zhang - Washington University in St. LouisJohn R. Osborne - Washington University in St. LouisLing Lin - Washington University in St. LouisMichelle O'Laughlin - Washington University in St. LouisJoshua F. McMichael - Washington University in St. LouisKim D. Delehaunty - Washington University in St. LouisSean D. McGrath - Washington University in St. LouisLucinda A. Fulton - Washington University in St. LouisVincent J. Magrini - Washington University in St. LouisTammi L. Vickery - Washington University in St. LouisJasreet Hundal - Washington University in St. LouisLisa L. Cook - The Genome Center, Washington University, St. Louis, MO, USAJoshua J. Conyers - Washington University in St. LouisGary W. Swift - Washington University in St. LouisJerry P. Reed - Washington University in St. LouisPatricia A. Alldredge - Washington University in St. LouisTodd Wylie - Washington University in St. LouisJason Walker - Washington University in St. LouisJoelle Kalicki-Veizer - Washington University in St. LouisMark A. Watson - Department of Pathology and Immunology, Siteman Cancer Center, Washington University, St. Louis, MO, USASharon Heath - Washington University in St. LouisWilliam D. Shannon - Washington University in St. LouisNobish Varghese - Washington University in St. LouisRakesh Nagarajan - Washington University in St. LouisPeter Westervelt - Washington University in St. LouisMichael H. Tomasson - Washington University in St. LouisDaniel C. Link - Washington University in St. LouisTimothy A. Graubert - Washington University in St. LouisJohn F. DiPersio - Washington University in St. LouisElaine R. Mardis - Washington University in St. LouisRichard K. Wilson - Washington University in St. Louis
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.116(21), pp.99-99
- DOI
- 10.1182/blood.V116.21.99.99
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 11/19/2010
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984363453502771
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