Nature Research€¦ · Web viewSupplementary Information. The mutational . onco. print. of...

Supplementary Information

The mutational oncoprint of recurrent cytogenetic abnormalities in adult

patients with de novo acute myeloid leukemia

Ann-Kathrin Eisfeld1,*, Krzysztof Mrózek1,*, Jessica Kohlschmidt1,2, Deedra Nicolet1,2,

Shelley Orwick3, Christopher J. Walker1, Karl W. Kroll3, James S. Blachly3, Andrew J. Carroll4,

Jonathan E. Kolitz5, Bayard L. Powell6, Eunice S. Wang7, Richard M. Stone8, Albert de la

Chapelle1, John C. Byrd3,#, and Clara D. Bloomfield1,#

1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

3. Division of Hematology, Department of Internal Medicine, The Ohio State University

Comprehensive Cancer Center, Columbus, OH, USA

4. University of Alabama at Birmingham, Birmingham, AL, USA

5. Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine,

Lake Success, NY, USA

6. Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA

7. Roswell Park Cancer Institute, Buffalo, NY, USA

8. Dana-Farber/Partners CancerCare, Boston, MA, USA

The authors declare no conflicts of interest.

* These authors contributed equally to this work.# These senior authors contributed equally to this work.

Running title: Mutational oncoprint of recurrent cytogenetic groups in AML

1

Participating institutions

The following Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in

Oncology (Alliance) institutions participated in this study and contributed at least five patients.

For each of these institutions, the current or last principal investigator and the cytogeneticists

who analyzed the cases are listed as follows:

The Ohio State University Medical Center, Columbus, OH: Richard M. Goldberg, Karl S. Theil,

Diane Minka and Nyla A. Heerema; North Shore University Hospital, Manhasset, NY: Daniel R.

Budman, Prasad R. K. Koduru, Ayala Aviram-Goldring and Chandrika Sreekantaiah; Wake

Forest University School of Medicine, Winston-Salem, NC: Heidi Klepin, P. Nagesh Rao,

Wendy L. Flejter and Mark Pettenati; Roswell Park Cancer Institute, Buffalo, NY: Ellis G.

Levine and AnneMarie W. Block; Dana Farber Cancer Institute, Boston, MA: Harold J. Burstein,

Ramana V. Tantravahi, Leonard L. Atkins, Cynthia C. Morton and Paola Dal Cin; Washington

University School of Medicine, St. Louis, MO: Nancy L. Bartlett, Michael S. Watson, Eric C.

Crawford, Jaime Garcia-Heras, Peining Li and Shashikant Kulkarni; University of Iowa

Hospitals, Iowa City, IA: Daniel A. Vaena and Shivanand R. Patil; University of Chicago

Medical Center, Chicago, IL: Hedy L. Kindler, Diane Roulston, Katrin M. Carlson, Yanming

Zhang and Michelle M. LeBeau; University of North Carolina, Chapel Hill, NC: Thomas C.

Shea and Kathleen W. Rao; Duke University Medical Center, Durham, NC: Jeffrey Crawford,

Sandra H. Bigner, Mazin B. Qumsiyeh, John Eyre and Barbara K. Goodman; University of

Maryland Cancer Center, Baltimore, MD: Martin J. Edelman, Joseph R. Testa, Maimon M.

Cohen, Judith Stamberg and Yi Ning; Dartmouth Medical School, Lebanon, NH: Konstantin

Dragnev, Doris H. Wurster-Hill and Thuluvancheri K. Mohandas; Rhode Island Hospital,

Providence, RI: Howard Safran, Teresita Padre-Mendoza, Jennifer A. Ahearn, Hon Fong L.

2

Mark, Shelly L. Kerman and Aurelia Meloni-Ehrig; Ft. Wayne Medical Oncology/Hematology,

Ft. Wayne, IN: Sreenivasa Nattam and Patricia I. Bader; Christiana Care Health Services, Inc.,

Newark, DE: Gregory Masters, Digamber S. Borgaonkar, Jeanne M. Meck, Kathleen Richkind

and Eduardo Cantu; Weill Medical College of Cornell University, New York, NY: Scott

Tagawa, Ram S. Verma, Prasad R.K. Koduru, Andrew J. Carroll and Susan Mathew; Western

Pennsylvania Hospital, Pittsburgh, PA: John Lister and Gerard R. Diggans; Massachusetts

General Hospital, Boston, MA: David Ryan, Justin Gainor, Leonard L. Atkins, Cynthia C.

Morton and Paola Dal Cin; University of Vermont Cancer Center, Burlington, VT: Claire

Verschraegen, Elizabeth F. Allen and Mary Tang; SUNY Upstate Medical University, Syracuse,

NY: Stephen L. Graziano, Larry Gordon and Constance K. Stein; Moores University of

California San Diego Cancer Center, San Diego, CA: Barbara A. Parker, Renée Bernstein and

Marie L. Dell'Aquila; Eastern Maine Medical Center, Bangor, ME: Thomas H. Openshaw,

Laurent J. Beauregard and Sarah South; Long Island Jewish Medical Center, Lake Success, NY:

Daniel R. Budman, Prasad R. K. Koduru, Ayala Aviram-Goldring and Chandrika Sreekantaiah;

University of Massachusetts Medical Center, Worcester, MA: William V. Walsh, Philip L.

Townes, Vikram Jaswaney, Kathleen Richkind, Michael J. Mitchell and Patricia Miron; Mount

Sinai School of Medicine, New York, NY: Lewis R. Silverman and Vesna Najfeld; Walter Reed

National Military Medical Center, Bethesda, MD: Mary Kwok, Rawatmal B. Surana, Digamber

S. Borgaonkar and Kathleen E. Richkind; University of Minnesota, Minneapolis, MN: Bruce A.

Peterson, Diane C. Arthur and Betsy A. Hirsch; University of Alabama at Birmingham,

Birmingham, AL: Robert Diasio and Andrew J. Carroll; University of Tennessee Cancer Center,

Memphis, TN: Harvey B. Niell and Sugandhi A. Tharapel; University of Illinois, Chicago, IL:

Arkadiusz Z. Dudek, Maureen M. McCorquodale, Kathleen E. Richkind and Valerie Lindgren;

University of Missouri/Ellis Fischel Cancer Center, Columbia, MO: Clint Kingsley, Jeffrey R.

3

Sawyer, Tim Hui-Ming Huang and Linda M. Pasztor; Virginia Commonwealth University,

Richmond, VA: Steven Grossman and Colleen Jackson-Cook; University of Puerto Rico, San

Juan, Puerto Rico: Eileen I. Pacheco, Ramana V. Tantravahi, Leonard L. Atkins, Cynthia C.

Morton and Paola Dal Cin; University of Nebraska Medical Center, Omaha, NE: Apar Ganti and

Warren G. Sanger; University of California at San Francisco, San Francisco, CA: Charalambos

Andreadis and Kathleen E. Richkind; Georgetown University Medical Center, Washington, DC:

Minnetta C. Liu, Jeanne M. Meck and Christine Bryke; Nevada Cancer Research Foundation

CCOP, Las Vegas, NV: John Ellerton and Marie L. Dell'Aquila.

4

Supplementary Table S1. Pretreatment clinical characteristics of patients with de novo acute myeloid leukemia, listed for the total

cohort and separately for the five major cytogenetic groups

Characteristic Alln = 1603

CN-AMLn = 716

Complex karyotypen = 137

CBF-AMLn = 177

Balanced rearrangements

n = 224

Unbalanced abnormalities

n = 349

Pa

Age, years <0.001

Median Range

52 17-85

53 17-83

57 18-84

41 18-74

48 17-84

58 19-85

Sex, n (%) <0.001

Male 914 (57) 370 (52) 92 (67) 105 (59) 128 (57) 219 (63)

Female 689 (43) 346 (48) 45 (33) 72 (41) 96 (43) 130 (37)

Race, n (%) 0.007

White 1376 (88) 638 (91) 114 (87) 139 (81) 186 (85) 299 (86)

Non-white 195 (12) 66 (9) 17 (13) 32 (19) 32 (15) 48 (14)

Hemoglobin, g/dl 0.02

Median Range

9.2 2.3-25.1

9.3 4.2-25.1

9.1 5.5-14.7

8.9 3.1-14.2

9.4 5.6-15.8

9.1 2.3-14.1

Platelet count, x109/l <0.001

Median Range

55 4-989

57 5-850

50 4-376

38 7-369

64 8-387

60 4-989

WBC, x109/l <0.001

5

Median Range

23.2 0.4-475.0

29.5 0.6-475.0

7.6 0.7-225.3

22.8 0.4-244.3

25.9 1.0-320.0

13.2 0.6-276.8

Blood blasts, % <0.001

Median Range

52 0-99

57 0-99

34 0-99

49 1-97

57 0-99

44 0-99

Bone marrow blasts, % <0.001

Median Range

66 0-99

68 0-99

58 13-98

56 2-95

72 12-97

64 0-97

Extramedullary involvement, n (%)

377 (25) 200 (29) 19 (15) 48 (28) 56 (27) 54 (17)<0.001

Abbreviations: n, number; CN-AML, cytogenetically normal acute myeloid leukemia; CBF-AML, core-binding factor AML; WBC, white blood

count.

a P-values are from Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for discrete variables. The P-values reported compare

the five major cytogenetic groups.

6

Supplementary Table S2. Frequencies of single gene mutations detected in patients with de novo acute myeloid leukemia, listed for the

total cohort and separately for the five major cytogenetic groups

Mutation frequenciesAll

n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

AKT1, n (%) 1.00

Mutated 6 (0) 2 (0) 2 (1) 0 (0) 1 (0) 1 (0)

Wild-type 1597 (100) 714 (100) 135 (99) 177 (100) 223 (100) 348 (100)

ARAF, n (%) 0.77

Mutated 8 (0) 7 (1) 0 (0) 1 (1) 0 (0) 0 (0)

Wild-type 1595 (100) 709 (99) 137 (100) 176 (99) 224 (100) 349 (100)

ASXL1, n (%) Mutated 112 (7) 44 (6) 7 (5) 2 (1) 15 (7) 44 (13)

<0.001

Wild-type 1491 (93) 672 (94) 130 (95) 175 (99) 209 (93) 305 (87)

ATM, n (%) 1.00

Mutated 11 (1) 7 (1) 0 (0) 1 (1) 1 (0) 2 (1)

Wild-type 1592 (99) 709 (99) 137 (100) 176 (99) 223 (100) 347 (99)

AXL, n (%) 1.00

Mutated 25 (2) 12 (2) 1 (1) 4 (2) 4 (2) 4 (1)

7


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

Wild-type 1578 (98) 704 (98) 136 (99) 173 (98) 220 (98) 345 (99)

BCL2, n (%) 1.00

Mutated 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Wild-type 1602 (100) 715 (100) 137 (100) 177 (100) 224 (100) 349 (100)

BCOR, n (%) <0.001

Mutated 83 (5) 27 (4) 6 (4) 1 (1) 18 (8) 31 (9)

Wild-type 1520 (95) 689 (96) 131 (96) 176 (99) 206 (92) 318 (91)

BCORL1, n (%) 0.96

Mutated 43 (3) 20 (3) 1 (1) 7 (4) 3 (1) 12 (3)

Wild-type 1560 (97) 696 (97) 136 (99) 170 (96) 221 (99) 337 (97)

BRAF, n (%) 0.16

Mutated 7 (0) 1 (0) 0 (0) 1 (1) 0 (0) 5 (1)

Wild-type 1596 (100) 715 (100) 137 (100) 176 (99) 224 (100) 344 (99)

BRD4, n (%) 0.56

Mutated 18 (1) 6 (1) 3 (2) 0 (0) 2 (1) 7 (2)

Wild-type 1585 (99) 710 (99) 134 (98) 177 (100) 222 (99) 342 (98)

8


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

BRINP3, n (%) 1.00

Mutated 24 (1) 10 (1) 2 (1) 2 (1) 5 (2) 5 (1)

Wild-type 1579 (99) 706 (99) 135 (99) 175 (99) 219 (98) 344 (99)

BTK, n (%) 1.00

Mutated 5 (0) 2 (0) 1 (1) 0 (0) 1 (0) 1 (0)

Wild-type 1598 (100) 714 (100) 136 (99) 177 (100) 223 (100) 348 (100)

CBL, n (%) 1.00

Mutated 29 (2) 14 (2) 0 (0) 2 (1) 3 (1) 10 (3)

Wild-type 1574 (98) 702 (98) 137 (100) 175 (99) 221 (99) 339 (97)

CCND1, n (%) 0.35

Mutated 8 (0) 4 (1) 2 (1) 2 (1) 0 (0) 0 (0)

Wild-type 1595 (100) 712 (99) 135 (99) 175 (99) 224 (100) 349 (100)

CCND2, n (%) 0.006

Mutated 17 (1) 6 (1) 0 (0) 8 (5) 2 (1) 1 (0)

Wild-type 1586 (99) 710 (99) 137 (100) 169 (95) 222 (99) 348 (100)

CEBPA, n (%) <0.001

9


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

Mutated 89 (6) 71 (12) 2 (2) 0 (0) 1 (1) 15 (5)

Wild-type 1286 (94) 540 (88) 118 (98) 177 (100) 172 (99) 279 (95)

CSNK1A1, n (%) 0.28

Mutated 3 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (1)

Wild-type 1600 (100) 716 (100) 137 (100) 177 (100) 224 (100) 346 (99)

10


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

CTNNB1, n (%) 1.00

Mutated 4 (0) 2 (0) 0 (0) 0 (0) 2 (1) 0 (0)

Wild-type 1599 (100) 714 (100) 137 (100) 177 (100) 222 (99) 349 (100)

DNMT3A, n (%) <0.001

Mutated 375 (23) 255 (36) 18 (13) 1 (1) 13 (6) 88 (25)

Wild-type 1228 (77) 461 (64) 119 (87) 176 (99) 211 (94) 261 (75)

DNMT3A R882, n (%) <0.001

Mutated 251 (16) 177 (25) 7 (5) 0 (0) 8 (4) 59 (17)

Wild-type 1352 (84) 539 (75) 130 (95) 177 (100) 216 (96) 290 (83)

DNMT3A non-R882, n (%)

<0.001

Mutated 126 (8) 80 (11) 11 (8) 1 (1) 5 (2) 29 (8)

Wild-type 1477 (92) 636 (89) 126 (92) 176 (99) 219 (98) 320 (92)

ETV6, n (%) 1.00

Mutated 40 (2) 15 (2) 5 (4) 3 (2) 5 (2) 12 (3)

Wild-type 1563 (98) 701 (98) 132 (96) 174 (98) 219 (98) 337 (97)

EZH2, n (%) 1.00

11

Mutated 45 (3) 18 (3) 1 (1) 4 (2) 7 (3) 15 (4)

Wild-type 1558 (97) 698 (97) 136 (99) 173 (98) 217 (97) 334 (96)

FBXW7, n (%) 0.60

Mutated 2 (0) 0 (0) 1 (1) 0 (0) 0 (0) 1 (0)

Wild-type 1596 (100) 716 (100) 135 (99) 177 (100) 222 (100) 346 (100)

FLT3-ITD, n (%) <0.001

Present 342 (22) 242 (35) 8 (6) 6 (3) 25 (12) 61 (18)

Absent 1213 (78) 458 (65) 128 (94) 168 (97) 185 (88) 274 (82)

FLT3-TKD, n (%) 0.27

Present 118 (7) 68 (10) 5 (4) 11 (6) 12 (5) 22 (6)

Absent 1467 (93) 647 (90) 128 (96) 166 (94) 209 (95) 317 (94)


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

GATA1, n (%) 1.00

Mutated 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0)

Wild-type 1602 (100) 716 (100) 137 (100) 177 (100) 224 (100) 348 (100)

GATA2, n (%) 0.003

Mutated 68 (4) 41 (6) 1 (1) 1 (1) 6 (3) 19 (5)

12

Wild-type 1535 (96) 675 (94) 136 (99) 176 (99) 218 (97) 330 (95)

GSK3B, n (%) 0.84

Mutated 8 (0) 2 (0) 2 (1) 0 (0) 2 (1) 2 (1)

Wild-type 1595 (100) 714 (100) 135 (99) 177 (100) 222 (99) 347 (99)

HIST1H1E, n (%) 1.00

Mutated 17 (1) 5 (1) 2 (1) 1 (1) 3 (1) 6 (2)

Wild-type 1586 (99) 711 (99) 135 (99) 176 (99) 221 (99) 343 (98)

HNRNPK, n (%) 1.00

Mutated 10 (1) 5 (1) 1 (1) 1 (1) 0 (0) 3 (1)

Wild-type 1593 (99) 711 (99) 136 (99) 176 (99) 224 (100) 346 (99)

IDH1, n (%) <0.001

Mutated 122 (8) 83 (12) 5 (4) 0 (0) 5 (2) 29 (8)

Wild-type 1480 (92) 633 (88) 132 (96) 177 (100) 219 (98) 319 (92)

IDH2, n (%) <0.001

Mutated R140 R172

181 (11)13942

94 (13)8212

8 (6)53

0 (0)00

8 (4)44

71 (20)4823

Wild-type 1422 (89) 622 (87) 129 (94) 177 (100) 216 (96) 278 (80)

IKZF1, n (%) 0.26

13

Mutated 25 (2) 8 (1) 2 (1) 0 (0) 5 (2) 10 (3)

Wild-type 1578 (98) 708 (99) 135 (99) 177 (100) 219 (98) 339 (97)

14


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

IKZF3, n (%) 1.00

Mutated 4 (0) 3 (0) 0 (0) 1 (1) 0 (0) 0 (0)

Wild-type 1599 (100) 713 (100) 137 (100) 176 (99) 224 (100) 349 (100)

IL7R, n (%) 0.34

Mutated 1 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0)

Wild-type 1600 (100) 716 (100) 135 (99) 177 (100) 223 (100) 349 (100)

JAK1, n (%) 1.00

Mutated 15 (1) 7 (1) 1 (1) 3 (2) 2 (1) 2 (1)

Wild-type 1588 (99) 709 (99) 136 (99) 174 (98) 222 (99) 347 (99)

JAK2, n (%) 0.51

Mutated 10 (1) 3 (0) 0 (0) 4 (2) 1 (0) 2 (1)

Wild-type 1539 (99) 699 (100) 128 (100) 173 (98) 212 (100) 327 (99)

JAK3, n (%) 0.96

Mutated 14 (1) 4 (1) 1 (1) 3 (2) 4 (2) 2 (1)

Wild-type 1589 (99) 712 (99) 136 (99) 174 (98) 220 (98) 347 (99)

KIT, n (%) <0.001

15

Mutated 51 (3) 4 (1) 3 (2) 35 (20) 3 (1) 6 (2)

Wild-type 1452 (97) 672 (99) 122 (98) 142 (80) 202 (99) 314 (98)

KLHL6, n (%) 1.00

Mutated 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Wild-type 1602 (100) 715 (100) 137 (100) 177 (100) 224 (100) 349 (100)

KMT2A, n (%) 0.06

Mutated 21 (1) 8 (1) 4 (3) 1 (1) 7 (3) 1 (0)

Wild-type 1582 (99) 708 (99) 133 (97) 176 (99) 217 (97) 348 (100)

KRAS, n (%) 0.003

Mutated 60 (4) 19 (3) 2 (1) 9 (5) 20 (9) 10 (3)

Wild-type 1541 (96) 697 (97) 134 (99) 168 (95) 204 (91) 338 (97)

16


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

MAPK1, n (%) 1.00

Mutated 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Wild-type 1602 (100) 715 (100) 137 (100) 177 (100) 224 (100) 349 (100)

MAPK3, n (%) 0.71

Mutated 4 (0) 1 (0) 1 (1) 1 (1) 1 (0) 0 (0)

Wild-type 1599 (100) 715 (100) 136 (99) 176 (99) 223 (100) 349 (100)

MED12, n (%) 0.48

Mutated 23 (1) 9 (1) 3 (2) 0 (0) 2 (1) 9 (3)

Wild-type 1580 (99) 707 (99) 134 (98) 177 (100) 222 (99) 340 (97)

MYD88, n (%) 1.00

Mutated 2 (0) 1 (0) 0 (0) 0 (0) 0 (0) 1 (0)

Wild-type 1601 (100) 715 (100) 137 (100) 177 (100) 224 (100) 348 (100)

NOTCH1, n (%) 0.46

Mutated 24 (1) 6 (1) 3 (2) 4 (2) 2 (1) 9 (3)

Wild-type 1579 (99) 710 (99) 134 (98) 173 (98) 222 (99) 340 (97)

NPM1, n (%) <0.001

17

Mutated 492 (31) 407 (57) 6 (5) 0 (0) 11 (5) 68 (20)

Wild-type 1086 (69) 305 (43) 123 (95) 177 (100) 207 (95) 274 (80)

NRAS, n (%) 0.02

Mutated 213 (13) 89 (12) 12 (9) 40 (23) 29 (13) 43 (12)

Wild-type 1390 (87) 627 (88) 125 (91) 137 (77) 195 (87) 306 (88)

PHF6, n (%) 0.21

Mutated 47 (3) 18 (3) 8 (6) 2 (1) 4 (2) 15 (4)

Wild-type 1556 (97) 698 (97) 129 (94) 175 (99) 220 (98) 334 (96)

PIK3CD, n (%) 1.00

Mutated 14 (1) 7 (1) 0 (0) 2 (1) 1 (0) 4 (1)

Wild-type 1589 (99) 709 (99) 137 (100) 175 (99) 223 (100) 345 (99)

18


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

PIK3CG, n (%) 1.00

Mutated 24 (1) 13 (2) 3 (2) 4 (2) 2 (1) 2 (1)

Wild-type 1579 (99) 703 (98) 134 (98) 173 (98) 222 (99) 347 (99)

PLCG2, n (%) 1.00

Mutated 39 (2) 15 (2) 4 (3) 2 (1) 9 (4) 9 (3)

Wild-type 1564 (98) 701 (98) 133 (97) 175 (99) 215 (96) 340 (97)

PLEKHG5, n (%) 1.00

Mutated 2 (0) 1 (0) 0 (0) 0 (0) 0 (0) 1 (0)

Wild-type 1588 (100) 712 (100) 133 (100) 177 (100) 222 (100) 344 (100)

PRKCB, n (%) 0.64

Mutated 17 (1) 5 (1) 4 (3) 3 (2) 2 (1) 3 (1)

Wild-type 1586 (99) 711 (99) 133 (97) 174 (98) 222 (99) 346 (99)

PRKD3, n (%) 1.00

Mutated 11 (1) 6 (1) 0 (0) 0 (0) 2 (1) 3 (1)

Wild-type 1592 (99) 710 (99) 137 (100) 177 (100) 222 (99) 346 (99)

PTEN, n (%) 0.20

19

Mutated 8 (0) 2 (0) 2 (1) 2 (1) 2 (1) 0 (0)

Wild-type 1595 (100) 714 (100) 135 (99) 175 (99) 222 (99) 349 (100)

PTPN11, n (%) 0.02

Mutated 101 (6) 59 (8) 5 (4) 1 (1) 15 (7) 21 (6)

Wild-type 1502 (94) 657 (92) 132 (96) 176 (99) 209 (93) 328 (94)

RAD21, n (%) 0.05

Mutated 33 (2) 24 (3) 0 (0) 4 (2) 2 (1) 3 (1)

Wild-type 1570 (98) 692 (97) 137 (100) 173 (98) 222 (99) 346 (99)

RAF1, n (%) 1.00

Mutated 10 (1) 6 (1) 1 (1) 0 (0) 1 (0) 2 (1)

Wild-type 1593 (99) 710 (99) 136 (99) 177 (100) 223 (100) 347 (99)

20


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

RUNX1, n (%) <0.001

Mutated 174 (11) 70 (10) 12 (9) 1 (1) 25 (11) 66 (19)

Wild-type 1429 (89) 646 (90) 125 (91) 176 (99) 199 (89) 283 (81)

SAMHD1, n (%) 1.00

Mutated 15 (1) 6 (1) 1 (1) 3 (2) 4 (2) 1 (0)

Wild-type 1588 (99) 710 (99) 136 (99) 174 (98) 220 (98) 348 (100)

SETBP1, n (%) 1.00

Mutated 38 (2) 20 (3) 2 (1) 1 (1) 5 (2) 10 (3)

Wild-type 1565 (98) 696 (97) 135 (99) 176 (99) 219 (98) 339 (97)

SF1, n (%) 1.00

Mutated 13 (1) 7 (1) 1 (1) 0 (0) 3 (1) 2 (1)

Wild-type 1590 (99) 709 (99) 136 (99) 177 (100) 221 (99) 347 (99)

SF3A1, n (%) 1.00

Mutated 15 (1) 6 (1) 0 (0) 2 (1) 1 (0) 6 (2)

Wild-type 1588 (99) 710 (99) 137 (100) 175 (99) 223 (100) 343 (98)

SF3B1, n (%) 0.03

21

Mutated 53 (3) 27 (4) 1 (1) 3 (2) 15 (7) 7 (2)

Wild-type 1550 (97) 689 (96) 136 (99) 174 (98) 209 (93) 342 (98)

SMARCA2, n (%) 1.00

Mutated 26 (2) 11 (2) 3 (2) 3 (2) 2 (1) 7 (2)

Wild-type 1577 (98) 705 (98) 134 (98) 174 (98) 222 (99) 342 (98)

SMC1A, n (%) 1.00

Mutated 59 (4) 30 (4) 2 (1) 3 (2) 8 (4) 16 (5)

Wild-type 1544 (96) 686 (96) 135 (99) 174 (98) 216 (96) 333 (95)

SMC3, n (%) 0.59

Mutated 50 (3) 31 (4) 3 (2) 3 (2) 7 (3) 6 (2)

Wild-type 1553 (97) 685 (96) 134 (98) 174 (98) 217 (97) 343 (98)

22


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

SRSF2, n (%) <0.001

Mutated 145 (9) 67 (9) 9 (7) 1 (1) 8 (4) 60 (17)

Wild-type 1446 (91) 647 (91) 124 (93) 175 (99) 215 (96) 285 (83)

STAG2, n (%) 0.08

Mutated 51 (3) 26 (4) 4 (3) 0 (0) 5 (2) 16 (5)

Wild-type 1552 (97) 690 (96) 133 (97) 177 (100) 219 (98) 333 (95)

SYK, n (%) 1.00

Mutated 11 (1) 6 (1) 0 (0) 2 (1) 1 (0) 2 (1)

Wild-type 1592 (99) 710 (99) 137 (100) 175 (99) 223 (100) 347 (99)

TET2, n (%) <0.001

Mutated 226 (14) 117 (16) 23 (17) 3 (2) 22 (10) 61 (17)

Wild-type 1377 (86) 599 (84) 114 (83) 174 (98) 202 (90) 288 (83)

TGM7, n (%) 1.00

Mutated 6 (0) 3 (0) 0 (0) 0 (0) 1 (0) 2 (1)

Wild-type 1577 (100) 705 (100) 132 (100) 176 (100) 220 (100) 344 (99)

TP53, n (%) <0.001

23

Mutated 73 (5) 2 (0) 52 (38) 0 (0) 13 (6) 6 (2)

Wild-type 1530 (95) 714 (100) 85 (62) 177 (100) 211 (94) 343 (98)

TYK2, n (%) 1.00

Mutated 32 (2) 12 (2) 4 (3) 4 (2) 3 (1) 9 (3)

Wild-type 1571 (98) 704 (98) 133 (97) 173 (98) 221 (99) 340 (97)

U2AF1, n (%) <0.001

Mutated 61 (4) 17 (2) 2 (1) 0 (0) 5 (2) 37 (11)

Wild-type 1542 (96) 699 (98) 135 (99) 177 (100) 219 (98) 312 (89)

WT1, n (%) Mutated 109 (7) 66 (9) 4 (3) 10 (6) 11 (5) 18 (5)

0.06

Wild-type 1494 (93) 650 (91) 133 (97) 167 (94) 213 (95) 331 (95)

24


n = 1603

CN-AML

n = 716


CBF-AML

n = 177


n = 224


n = 349

Pa

XPO1, n (%) 1.00

Mutated 7 (0) 5 (1) 0 (0) 0 (0) 0 (0) 2 (1)

Wild-type 1596 (100) 711 (99) 137 (100) 177 (100) 224 (100) 347 (99)

ZMYM3, n (%) 1.00

Mutated 2 (0) 1 (0) 0 (0) 0 (0) 1 (0) 0 (0)

Wild-type 1601 (100) 715 (100) 137 (100) 177 (100) 223 (100) 349 (100)

ZRSR2, n (%) 1.00

Mutated 82 (5) 34 (5) 10 (7) 7 (4) 14 (6) 17 (5)

Wild-type 1521 (95) 682 (95) 127 (93) 170 (96) 210 (94) 332 (95)

Total number of mutations

<0.001

Median Range

3 (0, 9)

3 (0, 9)

2 (0, 7)

1 (0, 5)

2 (0, 7)

3 (0, 9)

Abbreviations: n, number; CN-AML, cytogenetically normal acute myeloid leukemia; CBF-AML, core-binding factor AML.

a P-values are from Fisher’s exact test and compare the five major cytogenetic groups.

25

Supplementary Table S3. Proportions of patients with de novo acute myeloid leukemia classified into the five major cytogenetic groups

among patients aged <60 years and those aged ≥60 years

Major cytogenetic group Patients aged <60 years (n=1080)

Patients aged ≥60 years (n=523)

P-valuea

CN-AML, n (%) 485 (45) 234 (45) 0.96Complex karyotype, n (%) 76 (7) 61 (12) 0.003CBF-AML, n (%) 163 (15) 14 (3) <0.001Balanced rearrangements, n (%) 170 (16) 54 (10) 0.003Unbalanced rearrangements, n (%) 186 (17) 160 (31) <0.001

Abbreviations: n, number; CN-AML, cytogenetically normal acute myeloid leukemia; CBF-AML, core-binding factor AML.

a P-values are from Fisher’s exact test and compare older and younger AML patients.

26

Supplementary Table S4. Frequencies of gene mutations assigned to the functional groups detected in patients with cytogenetically

normal de novo acute myeloid leukemia, listed for the total cohort and separately for patients <60 and ≥60 years of age

Functional groupa Alln = 716

<60 yearsn = 484

≥60 yearsn = 232

Pb

Chromatin remodeling, n (%) 0.009

Mutated 105 (15) 59 (12) 46 (20)

Wild-type 611 (85) 425 (88) 186 (80)

Cohesin complex, n (%) 0.82

Mutated 110 (15) 73 (15) 37 (16)

Wild-type 606 (85) 411 (85) 195 (84)

Kinases, n (%) 0.05

Mutated 318 (46) 230 (49) 88 (41)

Wild-type 369 (54) 240 (51) 129 (59)

Methylation-related, n (%) <0.001

Mutated 438 (61) 266 (55) 172 (74)

Wild-type 278 (39) 218 (45) 60 (26)

NPM1, n (%) 0.26

Mutated 407 (57) 282 (59) 125 (54)

27


<60 yearsn = 484

≥60 yearsn = 232

Pb

Wild-type 305 (43) 199 (41) 106 (46)

RAS pathway, n (%) 0.09

Mutated 174 (24) 127 (26) 47 (20)

Wild-type 542 (76) 357 (74) 185 (80)

Spliceosome, n (%) <0.001

Mutated 136 (19) 49 (10) 87 (38)

Wild-type 578 (81) 433 (90) 145 (63)

Transcription factors, n (%) 0.01

Mutated 131 (21) 76 (18) 55 (27)

Wild-type 502 (79) 350 (82) 152 (73)

28


<60 yearsn = 484

≥60 yearsn = 232

Pb

Tumor suppressors, n (%) 0.81

Mutated 84 (12) 58 (12) 26 (11)

Wild-type 632 (88) 426 (88) 206 (89)

Abbreviation: n, number.a Chromatin remodeling is mutated if ASXL1, BCOR, BCORL1, EZH2 or SMARCA2 is mutated. Cohesin complex is mutated if RAD21, SMC1A,

SMC3 or STAG2 is mutated. Kinases is mutated if AXL, FLT3-ITD, FLT3-TKD, KIT or TYK2 is mutated. Methylation-related is mutated if

DNMT3A, IDH1, IDH2, or TET2 is mutated. NPM1 is mutated if NPM1 is mutated. RAS pathway is mutated if CBL, KRAS, NRAS or PTPN11 is

mutated. Spliceosome is mutated if SF3B1, SRSF2, U2AF1 or ZRSR2 is mutated. Transcription factors is mutated if CEBPA, ETV6, IKZF1,

GATA2, NOTCH1 or RUNX1 is mutated. Tumor suppressors is mutated if PHF6, TP53 or WT1 is mutated. b P-values are from Fisher’s exact test and compare patients aged <60 years with those aged ≥60 years.

29

Supplementary Table S5. Frequencies of gene mutations assigned to the functional groups detected in patients de novo acute myeloid

leukemia with complex karyotype, listed for the total cohort and separately for patients <60 and ≥60 years of age


<60 yearsn = 76

≥60 yearsn = 61

Pb


Mutated 17 (12) 12 (16) 5 (8)

Wild-type 120 (88) 64 (84) 56 (92)


Mutated 9 (7) 6 (8) 3 (5)

Wild-type 128 (93) 70 (92) 58 (95)

Kinases, n (%) 0.02

Mutated 19 (15) 15 (22) 4 (7)

Wild-type 106 (85) 53 (78) 53 (93)

Methylation-related, n (%) 0.85

Mutated 43 (31) 23 (30) 20 (33)

Wild-type 94 (69) 53 (70) 41 (67)

NPM1, n (%) 0.23

Mutated 6 (5) 5 (7) 1 (2)

30


<60 yearsn = 76

≥60 yearsn = 61

Pb

Wild-type 123 (95) 67 (93) 56 (98)


Mutated 19 (14) 14 (18) 5 (8)

Wild-type 118 (86) 62 (82) 56 (92)

Spliceosome, n (%) 0.008

Mutated 21 (16) 6 (8) 15 (25)

Wild-type 113 (84) 69 (92) 44 (75)


Mutated 22 (18) 12 (17) 10 (19)

Wild-type 101 (82) 57 (83) 44 (81)

31


<60 yearsn = 484

≥60 yearsn = 232

Pb


Mutated 63 (46) 30 (39) 33 (54)

Wild-type 74 (54) 46 (61) 28 (46)






32

Supplementary Table S6. Frequencies of gene mutations assigned to the functional groups detected in patients with de novo core-

binding factor acute myeloid leukemia, listed for the total cohort and separately for patients <60 and ≥60 years of age


<60 yearsn = 163

≥60 yearsn = 14

Pb


Mutated 16 (9) 14 (9) 2 (14)

Wild-type 161 (91) 149 (91) 12 (86)


Mutated 56 (32) 53 (33) 3 (21)

Wild-type 118 (68) 107 (67) 11 (79)

Kinases, n (%) 0.28

Mutated 4 (2) 3 (2) 1 (7)

Wild-type 173 (98) 160 (98) 13 (93)

Methylation-related, n (%) --

Mutated 0 (0) 0 (0) 0 (0)

Wild-type 177 (100) 163 (100) 14 (100)

NPM1, n (%) 0.23

Mutated 51 (29) 45 (28) 6 (43)

33


<60 yearsn = 163

≥60 yearsn = 14

Pb

Wild-type 126 (71) 118 (72) 8 (57)


Mutated 11 (6) 10 (6) 1 (7)

Wild-type 165 (94) 152 (94) 13 (93)


Mutated 8 (5) 8 (5) 0 (0)

Wild-type 169 (95) 155 (95) 14 (100)


Mutated 12 (7) 11 (7) 1 (7)

Wild-type 165 (93) 152 (93) 13 (93)

34


<60 yearsn = 484

≥60 yearsn = 232

Pb


Mutated 16 (9) 14 (9) 2 (14)

Wild-type 161 (91) 149 (91) 12 (86)






35

Supplementary Table S7. Frequencies of gene mutations assigned to the functional groups detected in patients with de novo acute

myeloid leukemia with balanced rearrangements, listed for the total cohort and separately for patients <60 and ≥60 years of age


<60 yearsn = 170

≥60 yearsn = 54

Pb


Mutated 42 (19) 28 (16) 14 (26)

Wild-type 182 (81) 142 (84) 40 (74)


Mutated 21 (9) 17 (10) 4 (7)

Wild-type 203 (91) 153 (90) 50 (93)

Kinases, n (%) 0.56

Mutated 45 (22) 32 (21) 13 (26)

Wild-type 156 (78) 119 (79) 37 (74)

Methylation-related, n (%) 0.02

Mutated 41 (18) 25 (15) 16 (30)

Wild-type 183 (82) 145 (85) 38 (70)

NPM1, n (%) 0.005

Mutated 11 (5) 4 (2) 7 (13)

36


<60 yearsn = 170

≥60 yearsn = 54

Pb

Wild-type 207 (95) 162 (98) 45 (87)


Mutated 65 (29) 56 (33) 9 (17)

Wild-type 159 (71) 114 (67) 45 (83)


Mutated 41 (18) 30 (18) 11 (21)

Wild-type 182 (82) 140 (82) 42 (79)


Mutated 39 (21) 28 (20) 11 (25)

Wild-type 143 (79) 110 (80) 33 (75)

37


<60 yearsn = 484

≥60 yearsn = 232

Pb


Mutated 26 (12) 21 (12) 5 (9)

Wild-type 198 (88) 149 (88) 49 (91)






38

Supplementary Table S8. Frequencies of gene mutations assigned to the functional groups detected in patients with de novo acute

myeloid leukemia with unbalanced rearrangements, listed for the total cohort and separately for patients <60 and ≥60 years of age


<60 yearsn = 187

≥60 yearsn = 161

Pb


Mutated 85 (24) 34 (18) 51 (31)

Wild-type 264 (76) 153 (82) 111 (69)


Mutated 41 (12) 22 (12) 19 (12)

Wild-type 308 (88) 165 (88) 143 (88)

Kinases, n (%) 0.005

Mutated 95 (30) 62 (37) 33 (22)

Wild-type 219 (70) 104 (63) 115 (78)

Methylation-related, n (%) <0.001

Mutated 188 (54) 77 (41) 111 (69)

Wild-type 161 (46) 110 (59) 51 (31)

NPM1, n (%) 0.007

Mutated 68 (20) 46 (25) 22 (14)

39


<60 yearsn = 187

≥60 yearsn = 161

Pb

Wild-type 274 (80) 135 (75) 139 (86)


Mutated 80 (23) 43 (23) 37 (23)

Wild-type 269 (77) 144 (77) 125 (77)

Spliceosome, n (%) < 0.001

Mutated 112 (32) 35 (19) 77 (48)

Wild-type 233 (68) 150 (81) 83 (52)


Mutated 101 (33) 47 (27) 54 (40)

Wild-type 207 (67) 125 (73) 82 (60)

40


<60 yearsn = 484

≥60 yearsn = 232

Pb


Mutated 38 (11) 23 (12) 15 (9)

Wild-type 311 (89) 164 (88) 147 (91)






41

Supplementary Figure S1. Oncoprint of mutations found in patients with de novo acute myeloid leukemia who had specific

cytogenetic findings, using only mutations which were detected with a VAF of ≥30%. The color coding of rows indicate the

assignment of recurrent cytogenetic abnormalities to five major cytogenetic groups. Columns represent single gene mutations that are

clustered into the previously described functional groups (Cancer Genome Atlas Research Network. N Engl J Med 2013; 368: 2059-

2074). The frequency of each mutation detected within a given cytogenetic subset is indicated by a black-to-white color gradient, with

black indicating a mutation frequency ≥50%, and white indicating a mutation frequency <1% of patients. In addition, the specific

frequencies (in percent) are indicated in each cell.

Supplementary Figure S2. Pie charts showing how frequently mutations in each functional group are the first, second, third, fourth,

fifth or later mutational events within individual patient samples (based on their VAFs).

Supplementary Figure S3. Oncoprint of mutations found in patients with de novo acute myeloid leukemia and monosomal karyotype

(Breems et al. J Clin Oncol 2008; 26: 4791-4797). Columns represent single gene mutations that are clustered into the previously

described functional groups (Cancer Genome Atlas Research Network. N Engl J Med 2013; 368: 2059-2074). The frequency of each

mutation detected in patients with monosomal karyotype is indicated by a black-to-white color gradient, with black indicating a

mutation frequency ≥50%, and white indicating a mutation frequency <1% of patients. In addition, the specific frequencies (in

42

percent) are indicated in each cell. The respective mutation frequencies observed in the total patient cohort (n=1603 patients) have

been added as a reference.

43

Supplementary Figure S1.

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