Mutations In the DNA Methyltransferase Gene DNMT3A Are Highly Recurrent In Patients with Intermediate Risk Acute Myeloid Leukemia, and Predict Poor Outcomes

• Published in: Blood 2010-11, Vol.116 (21), p.99-99
• Main Authors: Ley, Timothy J, Ding, Li, Walter, Matthew J., McLellan, Michael D., Lamprecht, Tamara, Larson, David E., Kandoth, Cyriac, Payton, Jacqueline E., Baty, Jack, Welch, John S., Harris, Christopher C., Lichti, Cheryl F., Townsend, R. Reid, Fulton, Robert S., Dooling, David J., Koboldt, Daniel C., Schmidt, Heather, Zhang, Qunyuan, Osborne, John R., Lin, Ling, O'Laughlin, Michelle, McMichael, Joshua F., Delehaunty, Kim D., McGrath, Sean D., Fulton, Lucinda A., Magrini, Vincent J., Vickery, Tammi L., Hundal, Jasreet, Cook, Lisa L., Conyers, Joshua J., Swift, Gary W., Reed, Jerry P., Alldredge, Patricia A., Wylie, Todd, Walker, Jason, Kalicki-Veizer, Joelle, Watson, Mark A., Heath, Sharon, Shannon, William D., Varghese, Nobish, Nagarajan, Rakesh, Westervelt, Peter, Tomasson, Michael H., Link, Daniel C., Graubert, Timothy A., DiPersio, John F., Mardis, Elaine R., Wilson, Richard K.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.99.99

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