Comprehensive profile of cytogenetics in 2308 Chinese children and adults with de novo acute myeloid leukemia

Blood Cells, Molecules, and Diseases 49 (2012) 107–113

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Comprehensive profile of cytogenetics in 2308 Chinese children and adults with de novo acute myeloid leukemia Xin Li ⁎, Xiaoqing Li, Wei Xie, Yanjie Hu, Juan Li, Wen Du, Wei Liu, Hongrui Li, Xiangjun Chen, Lannan Zhang, Junfeng Wang, Shiang Huang ⁎⁎ Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

a r t i c l e

i n f o

Article history: Submitted 26 October 2011 Available online 9 June 2012 (Communicated by S. Weissman, M.D., 1 May 2012) Keywords: Acute myeloid leukemia Additional cytogenetic abnormalities Chromosomal abnormalities Cytogenetics Molecular cytogenetics

a b s t r a c t Diagnostic cytogenetic and molecular analysis is recognized as the most valuable prognostic factor in acute myeloid leukemia (AML). Among 2516 consecutive Chinese patients with de novo AML, 2308 patients had successful cytogenetic results including 61 subclasses of cytogenetic abnormalities and 27 kinds of additional cytogenetic abnormalities. The incidence of t(15;17)(q22;q12) was highest (16.7% of 2308 patients), followed by t(8;21)(q22;q22) (15.1%), trisomy 8 (5.5%), loss of Y (4.5%), trisomy 21 (2.4%), inv(16)(p13q22) or t(16;16)(p13;q22) (2.1%), etc. In comparison to children, adults had higher incidence of normal karyotype (41.5% vs. 29.1%, P b 0.001) and lower incidences of t(8;21)(q22;q22) (13.4% vs. 25.8%, P b 0.001), t(9;11)(p22; q23) (0.2% vs. 1.2%, P = 0.001) and other 11q23 rearrangements (1.0% vs. 3.4%, P b 0.001). Among 349 AML patients with t(8;21)(q22;q22), 310 (35.5%) were found in 873 patients with M2. The t(15;17)(q22;q12) was exclusively observed in 386 (71.0%) of 544 patients with M3. In 48 AML patients with inv(16)(p13q22) or t(16;16)(p13;q22), 42 (15.2%) were detected in 276 patients with M4. Our study displayed the cytogenetic characteristics in a large series of Chinese patients with de novo AML. Our results revealed the similarities and differences of cytogenetic abnormalities existing between Chinese and western AML patients. © 2012 Elsevier Inc. All rights reserved.

Introduction Diagnostic cytogenetic and molecular analysis is generally recognized as the most valuable prognostic factor in acute myeloid leukemia (AML) [1–3]. The 2008 Revision of WHO Classification of AML includes 7 types of recurrent chromosomal translocations [t(8;21)(q22;q22)/ (RUNX1-RUNX1T1); inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/(CBFBMYH11); t(15;17)(q22;q12)/(PML-RARα); t(9;11)(p22;q23)/(MLLT3MLL); t(6;9)(p23;q34)/(DEK-NUP214); inv(3)(q21q26.2) or t(3;3)(q21; q26.2)/(RPN1-EVI1); and t(1;22)(p13;q13)/(RBM15-MKL1)] and two kinds of molecular markers [4]. The predictive significance of the established translocations above and recurrent unbalanced abnormalities such as monosomy 5/deletion of 5q [−5/del(5q)], monosomy 7/deletion of 7q [−7/del(7q)], trisomy 8 [+8], monosomy 9/deletion of 9q [−9/ del(9q)], and trisomy 21 [+21] in AML patients has been investigated

[5–14]. The association of treatment outcome with 54 cytogenetic subgroups has been comprehensively studied [15]. Cytogenetic profiles of common established balanced and unbalanced abnormalities in Chinese patients with de novo AML were described in two recent reports [16,17]. In present study, 61 subclasses of cytogenetic abnormalities including 45 subclasses of rare cytogenetic abnormalities in a series of 2308 Chinese patients with AML have been described. Associations of 27 kinds of additional cytogenetic abnormalities (ACA), age, FAB subgroups with 11 subclasses of major cytogenetic abnormalities were presented. Geographic heterogeneity in cytogenetic abnormalities between Chinese and western patients were comparatively analyzed.

Materials and methods Patients

⁎ Correspondence to: X. Li, Center for Stem Cell, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue #1277, Wuhan 430022, China. Fax: + 86 27 85729267. ⁎⁎ Correspondence to: S. Huang, Center for Stem Cell, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue #1277, Wuhan 430022, China. E-mail addresses: [email protected] (X. Li), [email protected] (S. Huang). 1079-9796/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bcmd.2012.05.007

From March 2003 to December 2010, genetic analyses of 2516 consecutive patients with de novo AML were performed at our Center. All cases were diagnosed and classified according to the FAB diagnostic criteria and the consensus guidelines for immunologic diagnosis of acute leukemia [18–21]. The lineage assignment of AML M0 and M7 was established by multiparameter flow cytometry at our Center as previously described [22].

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Cytogenetic and molecular genetic analyses Cytogenetic analysis was performed at our Center as previously described [23]. Briefly, bone marrow cells were cultured for 24 h to be prepared for conventional chromosome detection, and karyotype was analyzed with G-banding technique. Each karyotype was written according to International Human Chromosomes Nomenclature (ISCN 2009) [24]. RNA from bone marrow sample was prepared and reverse transcriptase polymerase chain reaction (RT-PCR) or quantitative RT-PCR (qRT-PCR) was performed using published primer sets for RUNX1-RUNX1T1, CBFB-MYH11, PML-RARα, dupMLL, and BCR-ABL1 as previously described [25–27]. Patients were classified as having an abnormal, normal, or failed cytogenetic results as follows [15]. A result was defined as normal after analysis of a minimum of 20 normal metaphases. Analysis of less than 20 normal metaphases was defined as a failure. A result was defined as an abnormal when a clonal chromosomal abnormality was observed. Karyotypes were classified according to classification scheme of the chromosome abnormalities in Grimwade et al.'s report [15]. Patients with adequate karyotypes were classified based on the presence of the chromosomal abnormalities observed in at least 5 patients [8,15]. Cases with none of these changes were classified as “other”. Five levels (1 to 5 or more) of karyotype complexities were defined based on the number of unrelated abnormalities [13,15]. Abnormality counting was based on Grimwade et al.'s definition [15]. Cases with two or more of cytogenetic abnormalities were classified as previously described [23]. When one patient had one of 6 types of the established translocations [inv(3)(q21q26) or t(3;3)(q21;q26), t(8;21)(q22;q22), t(9;22)(q34;q11), all 11q23 rearrangements, t(15;17) (q22;q12), and inv(16)(p13q22) or t(16;16)(p13;q22)] and other cytogenetic abnormalities, the established translocation was designated as major abnormality listed in the horizontal column of Table 2 and the remaining as ACA listed in the vertical column. When one patient without one of 6 types of the established translocations had −5/ del(5q), −7/del(7q), +8, −9/del(9q), and +21, in a ascending order, and other abnormalities, the first one [i.e. −5/del(5q)] was designated as major abnormality listed in the horizontal column of Table 2 and other abnormalities as ACA listed in the vertical column. Similarly, when one patient had −7/del(7q), +8, −9/9p−, +21 and other abnormalities, the first one [i.e. −7/del(7q)] was designated as major abnormality listed in the horizontal column of Table 2 and other abnormalities as ACA listed in the vertical column. And so on. These abnormalities were counted only once. Statistical analysis Comparisons of incidences of cytogenetic abnormalities and of levels of karyotype complexities between two age subgroups were performed using Pearson chi-square test. All statistic calculations were performed using the SPSS software package, version 16.0 (SPSS Inc., Chicago, IL, USA). Results Patient characteristics Between March 2003 and December 2010, genetic analyses of a total of 2516 consecutive patients with de novo AML were performed at our Center. Among these patients, 208 had failed cytogenetic results with b20 normal metaphases and 2308 (91.7%) had successful genetic results including 1021 (44.2%) females and 1287 (55.8%) males with a median age of 37 years (range 0.2–86 years). Among 2308 AML patients, a normal karyotype was detected in 918 (39.8%) and a cytogenetic abnormality in 1390 (60.2%) including 869 (37.7%) with the established chromosomal translocations, 177 (7.7%) with a sole unbalanced cytogenetic abnormality, and 344

(14.9%) with none of these changes above (defined as “other”). Results of RT-PCR or qRT-PCR showed that RUNX1-RUNX1T1 was expressed in 48 patients, BCR-ABL1 in 8, PML-RARA in 120, CBFBMYH11 in 8, dupMLL in 4, MLL/AF4 in 1 and MLL/AF6 in 1, respectively. Translocation of t(9;11)(p22;q23) was found in 7 patients. Thirty patients had other 11q23 rearrangements including t(1;11)(q21;q23) (n = 1), del(11)(q23)/MLL/AF4(+) (n = 1), t(5;11)(q13;q23) (n = 2), del(11)(q23)/MLL/AF6(+) (n=1), t(10;11)(p15;q23) (n=1), t(11;17) (q23;q21) (n=1), t(11;17)(q23;q25) (n=2), and 3-way translocation of t(6;17;11)(q13;q21;q23) (n=1). Distribution of 61 subclasses of cytogenetic abnormalities in AML Cytogenetic abnormalities were categorized into 61 subclasses and their individual incidences were listed in Table 1. Translocation of t(6;9)(p23;q34) in a sole abnormality was found in 4 (0.2%) patients. The 61 subclasses of cytogenetic abnormalities were divided into three levels according to their incidences. The highest prevalent cytogenetic abnormality was the translocation of t(15;17)(q22;q12) (16.7% of 2308 cases), followed by t(8;21)(q22;q22) (15.1%). Such cytogenetic abnormalities were detected in 1% to 9.9% of patients as +8 (5.5%), loss of Y (− Y) (4.5%), + 21 (2.4%), inv(16)(p13.1q22) or t(16;16)(p13.1;q22) (2.1%), loss of X (-X) (1.6%), del(7q) (1.5%), t(9;22)(q34;q11) (1.5%), del(5q) (1.4%), trisomy 22 [+22] (1.4%), other 11q23 rearrangements except for t(9;11)(p22;q23) (1.3%), −7 (1.2%), del(9q) (1.0%), and monosomy 17 [−17] (1.0%). The incidences of 45 subclasses of abnormalities were found in less than 1.0% of patients, designed as rare cytogenetic abnormalities. Associations of 27 kinds of ACA with 11 subclasses of major cytogenetic abnormalities Associations of 27 kinds of ACA with 11 subclasses of major cytogenetic abnormalities were presented in Table 2. The established balanced chromosomal translocations were mutually exclusive. The −5/del(5q) was observed in 36 patients with 2 or more abnormalities (Table 1). As an ACA, − 5/del(5q) was observed in 6 patients with t(8;21)(q22;q22) (n = 4), all 11q23 (n = 1), and t(15;17)(q22; q12) (n = 1). As a major cytogenetic abnormality, −5/del(5q) was found in 30 AML patients without one of the established translocations. The − 7/del(7q) (n = 7), − 17 (n = 6), and abnormality of 17p [abn(17p)] (n = 5) were ACA of these 30 patients with −5/del(5q). Loss of chromosome Y [− Y] was observed in 99 patients with 2 or more cytogenetic abnormalities (Table 1). Among these patients, 97 were presented in Table 2. The 3 most common additional cytogenetic abnormalities (ACA) in 11 subclasses of major cytogenetic abnormalities were summarized in Supplementary Table A.1. The −7/del(7q) was the most common ACA in patients with inv(3)(q21q26) or t(3;3)(q21;q26) (2/4, 50.0%) and with −5/del(5q) (7/30, 23.3%), respectively. Trisomy 21 (+21), as an ACA, was usually accompanied with + 8 (10/36, 27.8%). The isochromosome of 17q10 [i(17)(q10)] was found in 2 (20.0%) of 10 patients with t(9;22)(q34;q11). Trisomy 8 was the most common ACA in patients with all 11q23 (2/13, 15.4%) and with t(15;17)(q22;q12) (18/71, 25.4%), respectively. Trisomy 22 (+22), as an ACA, were frequently associated with inv(16)(p13q22) or t(16;16)(p13;q22) (12/25, 48.0%). Distribution of cytogenetic abnormalities in age-related subtypes of AML Distribution of cytogenetic abnormalities in 9 age-related subgroups of AML was outlined in Supplementary Table A.2. The highest incidences of AML occurred in patients aged 30–39 (17.6%) and 40–49 years (17.5%), respectively. Patients aged 10–19 years had highest incidence of t(8;21)(q22;q22) (26.8%), followed by patients aged 0–9 years (22.4%). All 11q23 rearrangements was more likely to

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Table 1 Frequency and demographics of cytogenetic abnormalities of 2308 patients with de novo acute myeloid leukemia. Chromosome involved

Cytogenetic abnormalities

No. of patients with cytogenetic abnormalities (%)

No. of patients with a sole abnormality (%)

No. of patients with 2 or more abnormalities (%)

– 1

Normal karyotype Abnormality of 1p Abnormality of 1q Duplication of 1q Abnormality of 3p inv(3)(q21q26) or t(3;3)(q21;q26) Trisomy 4 Deletion of 4q Trisomy 5 Monosomy 5 Deletion of 5q Trisomy 6 Monosomy 6 Abnormality of 6q not t(6;11)(q27;q23) Monosomy 7 Deletion of 7q Isochromosome of 7q10 Trisomy 8 Monosomy 8 t(8;21)(q22;q22) Abnormality of 8q Monosomy 9 t(9;11)(p22;q23) t(9;22)(q34;q11) Deletion of 9q Monosomy 10 Trisomy 11 other 11q23 Monosomy 12 Abnormality of 12p13 other abnormality of 12p13 Trisomy 13 Monosomy 13 Trisomy 14 Monosomy 14 Trisomy 15 Monosomy 15 t(15;17)(q22;q12) Abnormality of 15q, not t(15;17)(q22;q12) Monosomy 16 inv(16)(p13q22) or t(16;16)(p13;q22) Monosomy 17 Deletion of 17q Abnormality of 17p Isochromosome of 17q10 Trisomy 18 Monosomy 18 Addition of 18q Trisomy 19 Monosomy 19 Trisomy 20 Monosomy 20 Abnormality of 20q Trisomy 21 Monosomy 21 Abnormality of 21q, not t(8;21)(q22;q22) Trisomy 22 Monosomy 22 Deletion of 22q Loss of X Loss of Y Other

918 (39.8) 8 (0.3) 8 (0.3) 5 (0.2) 6 (0.3) 15 (0.6) 15 (0.6) 7 (0.3) 5 (0.2) 8 (0.3) 33 (1.4) 11 (0.5) 6 (0.3) 6 (0.3) 28 (1.2) 35 (1.5) 6 (0.3) 126 (5.5) 5 (0.2) 349 (15.1) 8 (0.3) 9 (0.4) 7 (0.3) 34 (1.5) 23 (1.0) 7 (0.3) 18 (0.8) 30 (1.3) 7 (0.3) 11 (0.5) 5 (0.2) 6 (0.3) 7 (0.3) 7 (0.3) 8 (0.3) 6 (0.3) 11 (0.5) 386 (16.7) 7 (0.3) 17 (0.7) 48 (2.1) 24 (1.0) 10 (0.4) 8 (0.3) 12 (0.5) 6 (0.3) 9 (0.4) 5 (0.2) 7 (0.3) 8 (0.3) 6 (0.3) 7 (0.3) 11 (0.5) 55 (2.4) 12 (0.5) 8 (0.3) 32 (1.4) 12 (0.5) 9 (0.4) 37 (1.6) 104 (4.5) 344 (14.9)

0 (0) 0 (0) 0 (0) 0 (0) 11 (73) 4 (27) 0 (0) 0 (0) 0 (0) 5 (15) 2 (18) 0 (0) 0 (0) 9 (32) 8 (23) 3 (50) 56 (44) 2 (40) 170 (49) 0 (0) 2 (22) 6 (86) 24 (71) 8 (35) 1 (14) 10 (56) 18 (60) 1 (14) 5 (45) 1 (20) 1 (17) 0 (0) 2 (29) 0 (0) 1 (17) 1 (9) 315 (82) 2 (29) 1 (6) 23 (48) 0 (0) 4 (40) 0 (0) 0 (0) 1 (17) 0 (0) 0 (0) 2 (29) 0 (0) 0 (0) 0 (0) 8 (73) 22 (40) 0 (0) 0 (0) 5 (16) 0 (0) 4 (44) 1 (3) 5 (5)

8 8 5 6 4 11 7 5 8 28 9 6 6 19 27 3 70 3 179 8 7 1 10 15 6 8 12 6 6 4 5 7 5 8 5 10 71 5 16 25 24 6 8 12 5 9 5 5 8 6 7 3 33 12 8 27 12 5 36 99

3 4 5

6

7

8

9

10 11 12

13 14 15

16 17

18

19 20

21

22

X Y

occur in children aged less than 10 years (7.7%). Patients aged 10– 49 years had higher incidence of t(15;17)(q22;q12) (ranging from 18.1% to 22.7%) than patients in other age subgroups (ranging from 4.8% to 14.1%). Similar incidences of inv(16)(p13q22) or t(16;16)(p13;q22) were observed in 8 age-related subtypes of AML (ranging from 0.5% to 3.2%) except for 80–89 years subgroup. Trisomy 21 was found in 44 of 341 patients aged 50–59 years with the highest incidence of 12.9%.

(100) (100) (100) (100) (27) (73) (100) (100) (100) (85) (82) (100) (100) (68) (77) (50) (56) (60) (51) (100) (78) (14) (29) (65) (86) (44) (40) (86) (55) (80) (83) (100) (71) (100) (83) (91) (18) (71) (94) (52) (100) (60) (100) (100) (83) (100) (100) (71) (100) (100) (100) (27) (60) (100) (100) (84) (100) (56) (97) (95)

Differential distribution of cytogenetic abnormalities in children and adults with AML Differential distribution of the established translocations, regardless of the presence of ACA, and the unbalanced cytogenetic abnormalities as a sole abnormality in Chinese children aged 0.2–15 years (n = 326) and adults aged 16–82 years (n = 1982) with AML was outlined in Table 3. In comparison to children, adults had higher incidence

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Table 2 Associations of 27 kinds of additional cytogenetic abnormalities (ACA) with 11 subclasses of major cytogenetic abnormalities in acute myeloid leukemia. ACA

+4 − 5/del(5q) +6 − 7/del(7q) +8 − 9/del(9q) − 10 + 11 abn(12p13) + 13 + 14 − 15 − 16 − 17 abn(17p) i(17)(q10) − 18 + 19 − 19 + 20 − 20 + 21 − 21 + 22 − 22 −X −Y

Major cytogenetic abnormalitiesa, n inv(3) n=4

− 5 and del(5q) n = 30

− 7 and del(7q) n = 23

+8 n = 36

− 9 and del(9q) n=6

t(8;21) n = 179

t(9;22) n = 10

11q23 n = 13

t(15;17) n = 71

inv(16) n = 25

+ 21 n = 12

Total

0 0 0 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0

0 – 1 7 2 0 1 2 2 1 0 2 4 6 5 1 1 0 3 1 3 1 2 2 4 0 0

1 0 0 – 2 0 1 0 1 1 2 3 2 3 1 1 3 0 3 0 2 1 3 2 2 0 0

4 0 4 0 – 0 0 3 0 2 2 1 2 0 0 0 0 1 0 1 1 10 0 3 1 0 0

0 0 0 0 0 – 1 0 0 0 0 0 0 1 1 0 0 0 0 1 0 0 0 1 0 0 0

4 4 1 8 2 12 2 0 0 1 0 0 1 1 0 0 0 2 1 1 0 4 1 0 1 32 94

0 0 0 0 1 0 0 0 1 0 0 0 0 1 0 2 0 1 0 0 0 0 1 1 0 0 1

0 1 0 0 2 2 1 0 0 0 0 0 1 1 0 1 1 1 0 1 0 0 0 0 1 0 1

0 1 1 4 18 1 0 0 1 0 0 1 0 1 0 5 0 0 0 1 0 3 0 1 0 0 1

0 0 1 2 6 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 12 0 0 0

2 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 – 0 2 0 0 0

11 6 8 23 34 16 6 5 5 5 5 7 10 14 7 10 5 5 7 6 6 21 7 25 9 32 97

a inv(3): inv(3)(q21q26) or t(3;3)(q21;q26). t(8;21): t(8;21)(q22;q22). t(9;22): t(9;22)(q34;q11). 11q23: all 11q23 rearrangements. t(15;17): t(15;17)(q22;q12). inv(16): inv(16)(p13q22) or t(16;16)(p13;q22).

of normal karyotype (41.5% vs. 29.1%, P b 0.001) and lower incidences of t(8;21)(q22;q22) (13.4% vs. 25.8%, P b 0.001), t(9;11)(p22;q23) (0.2% vs. 1.2%, P = 0.001) and other 11q23 rearrangements (1.0% vs. 3.4%, P b 0.001). Similar incidences of t(15;17)(q22;q12) (15.6% vs. 16.9%, P = 0.573) and inv(16)(p13q22) or t(16;16)(p13;q22) (3.1% vs. 1.9%, P = 0.177) were observed between children and adults. Although adults had higher incidences of +8 (2.7% vs. 0.9%) and +11 (0.5% vs. 0.0%) than children, the differences between them were not significant (P = 0.057 and 0.199, respectively). Levels of karyotype complexities in children and adults with AML were summarized in Table 3. Children with AML had higher incidence of 2 cytogenetic abnormalities and 4 cytogenetic abnormalities than their adult counterparts (P = 0.002, respectively). Differences of other levels of karyotype complexities (1 abnormality, 3 and 5 cytogenetic abnormalities) between children and adults were not significant (P = 0.099, 0.827 and 0.153, respectively). Distribution of cytogenetic abnormalities in FAB subtypes of AML Distribution of the established translocations, irrespective of the presence of ACA, and the unbalanced cytogenetic abnormalities as a sole abnormality in FAB subtypes (M0-M7) of AML was summarized in Supplementary Table A.3. Among 349 AML patients with t(8;21)(q22; q22), 310 (88.8%) were predominantly found in M2 subtype, 18 (5.2%) in M4, 11 (3.2%) in M1 and 10 (2.9%) in M5. In contrast, t(15;17)(q22; q12) was exclusively observed in 386 patients with M3. Fifteen AML patients with inv(3)(q21q26) or t(3;3)(q21;q26) were randomly distributed in M0 (n = 1, 6.7%), M1 (n = 1, 6.7%), M2 (n = 6, 40%), M4 (n = 4, 26.7%), M5 (n= 1, 6.7%), and M6 (n =2, 13.3%) subtypes except for M3 subtype. Thirty-seven patients with all 11q23 rearrangements were observed in 1 (2.7%) of 37 AML M0, in 5 (13.5%) of 246 M1, in 12

(32.4%) of 873 M2, in 12 (32.4%) of 276 M4 and in 6 (16.2%) of 225 M5 and in 1 (2.7%) of M6. In 48 AML patients with inv(16)(p13q22) or t(16;16)(p13;q22), 42 (87.5%) were mainly detected in M4 subtype, 3 (6.3%) in M5, 2 (4.2%) in M2 and 1 (2.1%) in M6. Successful cytogenetic results were available in 7 AML M7 patients and 3 of them had t(9;22)(q34;q11). Translocation of t(1;22)(p13;q13) was not seen in 7 AML M7 patients. Discussion Diagnostic cytogenetic and molecular analysis is generally recognized as the most valuable prognostic predictor in AML [1–3]. Cytogenetic profiles of common recurrent cytogenetic abnormalities in Chinese patients with de novo AML were described in two recent reports [16,17]. In this study, we present our cytogenetic results including 61 subclasses of cytogenetic abnormalities and 27 kinds of additional cytogenetic abnormalities (ACA), and compare our findings with others' reports in three aspects: ACA, age specific cytogenetic abnormalities and FAB subtype specific cytogenetic abnormalities. Chinese Epidemiologic Study Group of Leukemia and Aplastic Anemia made a nationwide incidence survey of leukemia in China in 1986–1988. The annual incidence of newly-diagnosed leukemia was 2.76 per 100,000 (1 670/60 557 127) [28]. There were 981 AML patients (58.7%) in 4 subtypes of leukemia and the incidence rate of AML was 1.62 per 100,000. Chen et al. made a regional incidence survey of leukemia in Nanjing, China [29]. The overall average annual incidence of de novo leukemia was 3.68/100,000 (1 095/29 760 300) in 2003–2007. There were 403 de novo AML cases (36.8%) with the incidence of 1.35 per 100,000. The age-adjusted incidences of leukemia and AML were 13.04 and 3.45 (26.5%) per 100,000 in the United States in 1975–2008,

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Table 3 Comparative profiles of cytogenetic abnormalities of Chinese patients and western cases with acute myeloid leukemia. Cytogenetic abnormalities

Chinese patientsa Children 326

Normal karyotype inv(3)(q21q26)/t(3;3)(q21;q26) − 7/del(7q) +8 t(8;21)(q22;q22) t(9;11)(p22;q23) t(9;22)(q34;q11) + 11 other 11q23 t(15;17)(q22;q12) inv(16)(p13q22)/t(16;16)(p13;q22) + 21

95 (29.1) 1 (0.3) 2 (0.6) 3 (0.9) 84 (25.8) 4 (1.2) 5 (1.5) 0 (0.0) 11 (3.4) 51 (15.6) 10 (3.1) 3 (0.9)

Western patients Adults

Children b

1982

1184

823 (41.5) 14 (0.7) 15 (0.8) 53 (2.7) 265 (13.4) 3 (0.2) 29 (1.5) 10 (0.5) 19 (1.0 ) 335 (16.9) 38 (1.9) 19 (1.0)

283 (23.9) 0 (0.0) 62 (5.2) 112 (9.5) 137 (11.6) 54 (6.4) 2 (0.2) 0 (0.0) 155 (13.1)f 117 (9.9) 70 (5.9) 60 (5.1)

Adults 633

c

156 (24.6) 0 (0.0) 48 (7.6) 81 (12.8) 86 (13.6) 40 (6.3) 0 (0.0) 0 (0.0) 104 (16.4)f 0 (0.0) 43 (6.8) 39 (6.2)

4257d

5876e

1922 (45.1) 85 (2.0) 356 (8.4) 387 (9.1) 235 (5.5) 27 (2.1) 34 (0.8) 0 (0.0) 141 (3.3)f 325 (7.6) 202 (4.7) 79 (2.2)

2432 (41.4) 69 (1.2) 424 (7.2) 547 (9.3) 421 (7.2) 61 (1.0) 47 (0.8) 81 (1.4) 150 (2.6) 788 (13.4) 284 (4.8) 148 (2.5)

Level of karyotype complexity 1 Abnormality 2 Abnormalities 3 Abnormalities 4 Abnormalities ≥ 5 Abnormalities a b c d e f

140 (42.9) 59 (18.1) 14 (4.3) 13 (4.0) 5 (1.5)

756 236 80 29 58

(38.1) (11.9) (4.0) (1.5) (2.9)

227 112 56 28 54

(35.9) (17.7) (8.8) (4.4) (8.5)

1830 (31.1) 786 (13.4) 275 (4.7) 123 (2.1) 430 (7.3)

Data from this study (n, %). Data from Mrózek et al.'s review including Leverger et al. (n = 130), Raimondi et al. (n = 121), Martinez-Climent et al. (n = 115), and Raimondi et al. (n = 478) [9]. Data from Harrison et al. [13]. Ninety-one patients with M3 were excluded from this study. Data from Mrózek et al.'s review including CALGB (n = 1311), MRC (n = 2337) and SWOG/ECOG (n = 609) [9]. Data from Grimwade et al. [15]. Data from all 11q23.

respectively [30]. The overall incidence of leukemia was 11.25 per 100,000 (4 162/36 993 338) in the U.K. in 1987–2006 [31]. The overall incidence and constituent ratio of AML were 1.63 per 100,000 (602/36 993 338) and 18.7% (602/3 226) in 6 subtypes of leukemia, respectively. Lower incidence of leukemia and higher constituent ratio of AML were found in Chinese population than those in western populations. The overall incidences of AML in China (1.62 per 100,000) and in U.K. (1.63 per 100,000) were similar, lower than that in the U.S.A. (3.45 per 100,000). Associations of 27 kinds of ACA with 11 subclasses of major cytogenetic abnormalities were described in our series in Table 2. We compared the distribution of ACA in AML patients in our series and in Grimwade et al.'s study [Table 4]. Among patients with 11 subclasses of major cytogenetic abnormalities, the most common ACA in patients with 9 subclasses of major cytogenetic abnormalities in these two studies were found to be the same, i.e. −7/del(7q) as most common ACA in patients with inv(3)(q21q26) or t(3;3)(q21;q26) and with −5/del(5q), respectively (Table 4). Table 4 Comparative profile of most common additional cytogenetic abnormalities of 1663 AML cases aged 16–59 years in our study and 5876 AML cases aged 16–59 years in Grimwade et al.'s study. Cytogenetic abnormalities

Overall, incidences of normal karyotype and 11 subclasses of cytogenetic abnormalities of Chinese childhood and adult patients with AML in four studies were similar except from t(8;21)(q22;q22) and inv(16)(p13q22) or t(16;16)(p13;q22) (Table 5). Incidence of t(8;21)(q22;q22) of patients in our series (15.1%) was highest. Whereas highest incidence of inv(16)(p13q22) or t(16;16)(p13; q22) was found in Tien's group (5.1%) [32]. Age is a crucial risk-stratification factor in AML [33–35]. Because the differences of incidences of normal karyotype, t(8;21)(q22;q22), t(9;11)(p22;q23) and other 11q23 rearrangements between Chinese children and adults with AML were significant (Table 3), they were designated as “age specific cytogenetic abnormalities”. Similar “age specific cytogenetic abnormalities” were also observed between western childhood and adults patients with AML (Table 3). Similar patterns of incidences of normal karyotype were found between Table 5 Comparative profiles of cytogenetic abnormalities of Chinese patients with acute myeloid leukemia. Variables

This study Patients Adults/children

Most common additional cytogenetic abnormalities This study

Grimwade et al.'s study [15]

inv(3)(q21q26)/ − 7/del(7q) (1/2, 50.0%) − 7/del(7q) (42/69, 60.9%) t(3;3)(q21;q26) − 5/del(5q) − 7/del(7q) (4/14, 28.6%) −7/del(7q) (119/275, 43.3%) − 7/del(7q) − 17 (2/16, 12.5% ) − 17 (59/424, 13.9%) +8 + 21 (8/24, 33.3%) + 21 (47/547, 8.6%) t(8;21)(q22;q22) − Y (73/129, 56.6%) −Y (137/421, 32.5%) − 9/del(9q) − 10 (1/4, 25.0%) − Y (20/158, 12.7%) t(9;22)(q34;q11) i(17)(q10) (1/7, 14.3%) − 7/del(7q) (7/47, 14.3%) all 11q23 + 8 (2/7, 28.6%) + 8 (26/211, 12.3%) t(15;17)(q22;q12) + 8 (16/58, 27.6%) + 8 (88/788, 11.2%) inv(16)(p13q22)/ + 22 (10/19, 52.6%) + 22 (55/284, 19.4%) t(16;16)(p13;q22) + 21 + 22 (2/7, 28.6%) + 22 (29/148, 19.6%)

Cytogenetic abnormalities (n, %)

Normal karyotype inv(3)(q21q26)/ t(3;3)(q21;q26) − 7/del(7q) 63 (2.7) +8 126 (5.5) t(8;21)(q22;q22) 349 (15.1) t(9;11)(p22;q23) 7 (0.3) t(9;22)(q34;q11) 34 (1.5) + 11 18 (0.8) other 11q23 30 (1.3) t(15;17)(q22;q12) 386 (16.7) inv(16)(p13q22)/ 48 (2.1) t(16;16)(p13;q22) + 21 55 (2.4) a

Data from all 11q23.

Cheng et al. [16] So et al. [17] Tien et al. [32]

2308 1293 1982/326 1157/136 (6.1:1) (8.5:1) 919 (39.8) 547 (42.3) 15 (0.6) 0 (0.0)

629 549/80 (6.9:1) 245 (39.0) 8 (1.3)

235 191/44 (4.3:1) 84 (35.7) 0 (0.0)

18 (1.6) 26 (2.0) 109 (8.4) 0 (0.0) 23 (1.8) 0 (0.0) 16 (1.2)a 187 (14.5) 0 (0.0)

28 (4.5) 25 (4.0) 54 (8.6) 5 (0.8) 1 (0.2) 3 (0.5) 4 (0.6) 98 (15.6) 18 (2.9)

5 (2.1) 5 (2.1) 25 (10.6) 3 (1.3) 7 (3.0) 3 (1.3) 5 (2.1) 35 (14.9) 12 (5.1)

21 (1.6)

7 (1.1)

2 (0.9)

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X. Li et al. / Blood Cells, Molecules, and Diseases 49 (2012) 107–113

Table 6 Comparative profiles of normal karyotype and 4 subclasses of cytogenetic abnormalities of Chinese, Japanese and Australian adults with acute myeloid leukemia. Cytogenetic abnormalities

Normal karyotype t(8;21)(q22;q22) All 11q23 t(15;17)(q22;q12) inv(16)(p13q22)/ t(16;16)(p13;q22) a b

Chinesea

Japaneseb

Australianb

1982 (16–82 years)

436 (16–91 years)

230 (16–86 years)

823 265 22 335 38

189 (43.3) 58 (13.3) 10 (2.3) 49 (11.2) 12 (2.8)

102 12 6 27 14

(41.5) (13.4) (1.2) (16.9) (1.9)

(44.4) (5.2) (2.6) (11.7) (6.1)

Data from this study (n, %). Data from Nakase et al. [36].

studies; similar to those in Japanese (33.1%, 53/160) adults [36] and Tien's (33.8%) study, respectively (Supplementary Table A.4). The 2010 Chinese population census announced that there are 1,339,724,852 persons in 31 provinces in China Mainland [40]. Patients with de novo AML in our study came from 14 provinces (45.2%) including 758,727,732 persons (56.6%). Therefore, cytogenetic profile in our study represents the distributional characteristics of cytogenetic abnormalities in the whole of China to a great degree. Our findings revealed the similarities and differences of incidences of cytogenetic abnormalities existing between Chinese and western AML patients. Correlation of cytogenetic subclasses with prognosis in AML patients remains investigating later. Authorship and disclosures

Chinese (29.1%) and western children (23.9%–24.6%) and between Chinese (41.5%) and western adults (41.4%–45.1%), respectively. Incidences of t(8;21)(q22;q22) in Chinese children (25.8%) and adults (13.4%) were about twice as those in western children (11.6%– 13.6%) and adults (5.5%–7.2%), respectively. In contrast, Chinese children and adults (4.6% and 1.2%) had much lower incidence of all 11q23 rearrangements than western children and adults (13.1%– 16.4% and ~3%). Chinese children and adults had higher incidences of t(9;22)(q34;q11) (1.5% and 1.5% vs. 0.2% and 0.8%), t(15;17) (q22;q12) (15.6% and 16.9% vs. 9.9% and 7.6%–13.4%) and lower incidences of inv(16)(p13q22) or t(16;16)(p13;q22) (3.1% and 1.9% vs. 5.9%–6.8% and 4.7%–4.8%) than western counterparts, respectively. Chinese children and adults had much lower incidences of −7/del(7q), +8, and +21 than western cases (Table 3). Patients with AML and 3 or more cytogenetic abnormalities consisted of 9.8% of children and 8.5% of adults in our series, respectively (Table 3). On the contrary, patients with AML and 3 or more cytogenetic abnormalities were observed in 21.8% of western children and in 14.1% of western adults, respectively. Incidences of normal karyotype and 4 subclasses of cytogenetic abnormalities of Chinese, Japanese and Australian adults with AML were displayed in Table 6 [36]. Incidences of normal karyotype and all 11q23 of Chinese, Japanese and Australian adults were similar. Lower incidence of t(8;21)(q22;q22) (5.2%) and higher incidence of inv(16)(p13q22) or t(16;16)(p13;q22) (6.1%) were observed in Australian adults than those in Chinese adults (13.4% and 1.9%), and in Japanese adults (13.3% and 2.8%), respectively. Chinese adults had higher incidence of t(15;17)(q22;q12) (16.9%) than Japanese (11.2%) and Australian (11.7%) adults. The distributional patterns of AML FAB subtypes in Chinese and western patients with AML were presented in Supplementary Table A.4 [16,17,28,37,38]. The composition ratios of M0, M2, M6 and M7 of AML in Chinese patients and western patients were similar. The ratios of M1 in Chinese cases (~ 10%) were lower than those in western cases (~ 20%). On the contrary, the ratios of M3 in Chinese cases (~20%) were higher than those in western cases (~10%). Two levels of ratios of M4 were found in Chinese patient (~ 6% and ~12%, respectively), lower than those in western patients (20%–30%). Two levels of ratios of M5 were also observed in Chinese patients (~10% and ~23%, respectively). The ratio of M5 in western patients was about 10%. As to FAB subtype specific cytogenetic abnormalities, incidence of t(15;17)(q22;q12) in M3 in our series (71.0%) was higher than that in Cheng et al.'s study (56.0%) [16], similar to those in Japanese (75.4%, 49/65) and Australian (78.1%, 25/32) adults in Nakase et al.'s study [36]; and lower than those in So et al.'s (89.9%) [17], Grimwade et al.'s (91.5%, 559/611) [39] and Tien et al.'s (97.2%) studies [32] (Supplementary Table A.4). Incidence of inv(16)(p13.1q22) or t(16;16) (p13.1;q22) in M4 in our series (15.2%) was lower than those in So's (20.3%) and Tien's (24.4%) studies (Supplementary Table A.4). Incidence of t(8;21)(q22;q22) in M2 in our study (35.5%) was higher than those Australian (15.3%, 9/59) adults [36], in Cheng's (22.1%) and So's (26.5%)

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