DNMT3A mutations in acute myeloid leukemia

Timothy J. Ley, Li Ding, Matthew J. Walter, Michael D. McLellan, Tamara Lamprecht, David E. Larson, Cyriac Kandoth, Jacqueline E. Payton, Jack Baty, John Welch, Christopher C. Harris, Cheryl F. Lichti, R. Reid Townsend, Robert S. Fulton, David J. Dooling, Daniel C. Koboldt, Heather Schmidt, Qunyuan Zhang, John R. Osborne, Ling Lin & 28 others Michelle O'Laughlin, Joshua F. McMichael, Kim D. Delehaunty, Sean D. McGrath, Lucinda A. Fulton, Vincent J. Magrini, Tammi L. Vickery, Jasreet Hundal, Lisa L. Cook, Joshua J. Conyers, Gary W. Swift, Jerry P. Reed, Patricia A. Alldredge, Todd Wylie, Jason Walker, Joelle Kalicki, Mark A. Watson, Sharon Heath, William D. Shannon, Nobish Varghese, Rakesh Nagarajan, Peter Westervelt, Michael H. Tomasson, Daniel C. Link, Timothy A. Graubert, John F. DiPersio, Elaine R. Mardis, Richard K. Wilson

Research output: Contribution to journalArticle

1191 Citations (Scopus)

Abstract

Background: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Methods: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. Results: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. Conclusions: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)

Original languageEnglish (US)
Pages (from-to)2424-2433
Number of pages10
JournalNew England Journal of Medicine
Volume363
Issue number25
DOIs
StatePublished - Dec 16 2010
Externally publishedYes

Fingerprint

Acute Myeloid Leukemia
Mutation
Cytogenetics
High-Throughput Nucleotide Sequencing
National Institutes of Health (U.S.)
Methyltransferases
Missense Mutation
Karyotype
DNA Sequence Analysis
Exons
Genome
Amino Acids
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., ... Wilson, R. K. (2010). DNMT3A mutations in acute myeloid leukemia. New England Journal of Medicine, 363(25), 2424-2433. https://doi.org/10.1056/NEJMoa1005143

DNMT3A mutations in acute myeloid leukemia. / 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; 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, 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.

In: New England Journal of Medicine, Vol. 363, No. 25, 16.12.2010, p. 2424-2433.

Research output: Contribution to journalArticle

Ley, TJ, Ding, L, Walter, MJ, McLellan, MD, Lamprecht, T, Larson, DE, Kandoth, C, Payton, JE, Baty, J, Welch, J, Harris, CC, Lichti, CF, Townsend, RR, Fulton, RS, Dooling, DJ, Koboldt, DC, Schmidt, H, Zhang, Q, Osborne, JR, Lin, L, O'Laughlin, M, McMichael, JF, Delehaunty, KD, McGrath, SD, Fulton, LA, Magrini, VJ, Vickery, TL, Hundal, J, Cook, LL, Conyers, JJ, Swift, GW, Reed, JP, Alldredge, PA, Wylie, T, Walker, J, Kalicki, J, Watson, MA, Heath, S, Shannon, WD, Varghese, N, Nagarajan, R, Westervelt, P, Tomasson, MH, Link, DC, Graubert, TA, DiPersio, JF, Mardis, ER & Wilson, RK 2010, 'DNMT3A mutations in acute myeloid leukemia', New England Journal of Medicine, vol. 363, no. 25, pp. 2424-2433. https://doi.org/10.1056/NEJMoa1005143
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. New England Journal of Medicine. 2010 Dec 16;363(25):2424-2433. https://doi.org/10.1056/NEJMoa1005143
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 ; 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, 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. / DNMT3A mutations in acute myeloid leukemia. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 25. pp. 2424-2433.
@article{49a4efa64b7a4e359c8d4ca2aa4842b4,
title = "DNMT3A mutations in acute myeloid leukemia",
abstract = "Background: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Methods: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. Results: A total of 62 of 281 patients (22.1{\%}) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7{\%}) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. Conclusions: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)",
author = "Ley, {Timothy J.} and Li Ding and Walter, {Matthew J.} and McLellan, {Michael D.} and Tamara Lamprecht and Larson, {David E.} and Cyriac Kandoth and Payton, {Jacqueline E.} and Jack Baty and John Welch and Harris, {Christopher C.} and Lichti, {Cheryl F.} and Townsend, {R. Reid} and Fulton, {Robert S.} and Dooling, {David J.} and Koboldt, {Daniel C.} and Heather Schmidt and Qunyuan Zhang and Osborne, {John R.} and Ling Lin and Michelle O'Laughlin and McMichael, {Joshua F.} and Delehaunty, {Kim D.} and McGrath, {Sean D.} and Fulton, {Lucinda A.} and Magrini, {Vincent J.} and Vickery, {Tammi L.} and Jasreet Hundal and Cook, {Lisa L.} and Conyers, {Joshua J.} and Swift, {Gary W.} and Reed, {Jerry P.} and Alldredge, {Patricia A.} and Todd Wylie and Jason Walker and Joelle Kalicki and Watson, {Mark A.} and Sharon Heath and Shannon, {William D.} and Nobish Varghese and Rakesh Nagarajan and Peter Westervelt and Tomasson, {Michael H.} and Link, {Daniel C.} and Graubert, {Timothy A.} and DiPersio, {John F.} and Mardis, {Elaine R.} and Wilson, {Richard K.}",
year = "2010",
month = "12",
day = "16",
doi = "10.1056/NEJMoa1005143",
language = "English (US)",
volume = "363",
pages = "2424--2433",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "25",

}

TY - JOUR

T1 - DNMT3A mutations in acute myeloid leukemia

AU - Ley, Timothy J.

AU - Ding, Li

AU - Walter, Matthew J.

AU - McLellan, Michael D.

AU - Lamprecht, Tamara

AU - Larson, David E.

AU - Kandoth, Cyriac

AU - Payton, Jacqueline E.

AU - Baty, Jack

AU - Welch, John

AU - Harris, Christopher C.

AU - Lichti, Cheryl F.

AU - Townsend, R. Reid

AU - Fulton, Robert S.

AU - Dooling, David J.

AU - Koboldt, Daniel C.

AU - Schmidt, Heather

AU - Zhang, Qunyuan

AU - Osborne, John R.

AU - Lin, Ling

AU - O'Laughlin, Michelle

AU - McMichael, Joshua F.

AU - Delehaunty, Kim D.

AU - McGrath, Sean D.

AU - Fulton, Lucinda A.

AU - Magrini, Vincent J.

AU - Vickery, Tammi L.

AU - Hundal, Jasreet

AU - Cook, Lisa L.

AU - Conyers, Joshua J.

AU - Swift, Gary W.

AU - Reed, Jerry P.

AU - Alldredge, Patricia A.

AU - Wylie, Todd

AU - Walker, Jason

AU - Kalicki, Joelle

AU - Watson, Mark A.

AU - Heath, Sharon

AU - Shannon, William D.

AU - Varghese, Nobish

AU - Nagarajan, Rakesh

AU - Westervelt, Peter

AU - Tomasson, Michael H.

AU - Link, Daniel C.

AU - Graubert, Timothy A.

AU - DiPersio, John F.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

PY - 2010/12/16

Y1 - 2010/12/16

N2 - Background: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Methods: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. Results: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. Conclusions: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)

AB - Background: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Methods: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. Results: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. Conclusions: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)

UR - http://www.scopus.com/inward/record.url?scp=78649906060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649906060&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1005143

DO - 10.1056/NEJMoa1005143

M3 - Article

VL - 363

SP - 2424

EP - 2433

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 25

ER -