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Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population

  • Hui Wei1,
  • Ying Wang1,
  • Chunlin Zhou1,
  • Dong Lin1,
  • Bingcheng Liu1,
  • Kaiqi Liu1,
  • Shaowei Qiu1,
  • Benfa Gong1,
  • Yan Li1,
  • Guangji Zhang1,
  • Shuning Wei1,
  • Xiaoyuan Gong1,
  • Yuntao Liu1,
  • Xingli Zhao1,
  • Runxia Gu1,
  • Yingchang Mi1 and
  • Jianxiang Wang1, 2Email author
Journal of Hematology & Oncology201811:18

https://doi.org/10.1186/s13045-018-0566-8

Received: 15 December 2017

Accepted: 2 February 2018

Published: 10 February 2018

Abstract

Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.

Keywords

Acute myeloid leukemiaMutationCore binding factorFLT3-ITD

Acquired genetic abnormalities play an essential role in leukemogenesis and are one of the most important prognostic factors in acute myeloid leukemia (AML). To investigate whether there are some distinctions in genetic alteration profiles among different human races, data from several prospective AML trials were retrospectively analyzed. The ratio of core binding factor (CBF) leukemia in our cohort (ChiCTR-TRC-10001202) is 27.7%. Similarly, the ratios are 22.1, 21.1, and 23.4%, respectively, from Chinese, Korean, and Japanese, the other three Eastern Asian AML cohorts [13]. However, the CBF leukemia constitutes 15.5, 12.5, 9.3, 10.2, and 12% of patients, respectively, in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003(Additional file 1: Table S1) [48]. All of the latter cohorts are from European or American countries. Therefore, CBF leukemia occurs more frequently in Eastern Asian countries than in European and American countries. Meanwhile, the proportion of NPM1 is 15.9 and 13.3%, respectively, in our cohort and another Chinese one [3] (Additional file 1: Table S2). The proportions of FLT3-ITD mutation are 11.2 and 13.0%, respectively, in our cohort and another Chinese one [3] (Additional file 1: Table S3). Whereas, NPM1 mutation ratios are 27.9, 29.0, and 33.0%, respectively, in MRC AML15, UK NCRI AML17, and German AML2003. FLT3-ITD mutation occurs at 24.6 and 17.9%, respectively, in MRC AML15 and UK NCRI AML17 (Additional file 1: Table S2 and S3) [5, 6, 8]. These data demonstrate that NPM1 and FLT3-ITD mutations are less common in Chinese AML patients in comparison with cases from Europe. It indicates that there are some differences in the frequencies of genetic alteration between Caucasian and Eastern Asian population.

The bias of these comparisons result from the fact that patients from Chinese and Korean cohorts are younger than those from European and American cohorts. To eliminate this bias, we only compared the molecular mutation constitution from patients younger than who were 40 years old in MRC AML10 and AML12 [912]. As shown in Table 1, all of the molecular mutations, except FLT3-TKD, are significantly different between MRC cohorts and ours. After excluding the age bias, the ratio of FLT3-ITD mutation is still higher in MRC cohorts, which is similar to the results based on the entire cohorts. And there are more DNMT3a mutations and less CEBPA mutations in MRC cohorts.
Table 1

Molecular mutation ratios of patients younger than 40 years old in MRC AML10 and AML12 and our cohort

 

MRC AML10 and AML12

China1a

P value (MRC vs. China1)

Age range, years

MUT, no.

WT, No.

MUT/total, %

Median age (range), years

MUT, no.

WT, No.

MUT/total, %

FLT3-ITD [9]

15–34

68

222

23.4

36 (15–55)

66

522

11.2

< 0.001

FLT3-TKD [10]

15–39

46

412

10.0

36 (15–55)

51

534

8.72

0.464

DNMT3a [11]

15–39

71

287

19.8

36 (15–55)

38

348

9.84

< 0.001

CEBPA [12]

15–39

49

524

8.6

36 (15–55)

116

442

20.8

< 0.001

CEBPA double [12]

15–39

33

540

5.8

36 (15–55)

75

483

13.4

< 0.001

CEBPA single [12]

15–39

16

557

2.9

36 (15–55)

41

517

7.3

< 0.001

Abbreviations: WT wild type, MUT Mutant

aData from our cohort (ChiCTR-TRC-10001202)

In order to further confirm that these differences were not due to the onset of age, we analyzed the data in patients older than 40 or 50 years old from Chinese and Japanese trials and compared with Caucasian data. As shown in Additional file 1: Table S4, the frequency of FLT3-ITD in patients older than 40 years old from Chinese trial is only 11.5% which is still significantly lower than that in MRC AML15 and UK NCRI AML17 trial (24.6 and 17.9%, respectively) [5, 6]. There are 24.4 and 18.7% CBF leukemia in patients older than 40 or 50 years old of Chinese and Japanese trials, respectively. They are all significantly higher than those from Caucasian trials, except that the difference between Japanese trials and ECOG1900 did not reach the threshold of statistical significance (Additional file 1: Table S5). NPM1 mutation occurs in 23.6% patients older than 40 years old from Chinese trial. It is still lower than Caucasian data, although there is only statistically difference in comparison with German AML2003 (P = 0.005) (Additional file 1: Table S6). These data suggest that AML patients older than 40 years old still had distinctions in frequencies of CBF and FLT3-ITD alterations, which is similar to the difference among the entire cohorts.

As we know, CBF alteration comprises CBFbeta-MYH11 and AML1-ETO fusion genes. Therefore, we finally compared and contrasted the CBF leukemia constitution between Eastern Asian and Caucasian trials. As shown in Table 2, CBFbeta-MYH11 occurred in 50.0 and 54.3% of CBF leukemia in HOVON/SAKK AML- 42 and ECOG1900 trials, respectively [4, 7]. There are only 20.1 and 20.8% CBFbeta-MYH11 in Chinese and Japanese trials, respectively [13], which are significantly lower than Caucasian data. We also calculated the frequencies in older patients in Eastern Asian trials. The CBFbeta-MYH11 ratios are 25.9 and 20.2% in AML patients older than 40 or 50 years old in Chinese and Japanese trials, respectively, which are also significantly lower than that in HOVON/SAKK AML- 42 and ECOG1900 trials and similar to the results of the entire cohort analysis (Table 2). These data indicate that both CBF leukemia frequencies and CBF leukemia constitutions are distinct between Eastern Asian and Caucasian trials, not only in the entire cohorts but also in post hoc analysis after excluding the age bias. We followed the outcome of all these cohorts after we found different mutation landscape. But we only showed, but did not compare the outcome between these cohorts since it is too complicated to compare the outcomes when patients received different therapies (Additional file 1: Table S7).
Table 2

CBF leukemia constitution in Japanese and Chinese cohorts against European and American cohorts

 

China1a

JALSG AML95, 97, and 201 [13]

China1a

JALSG AML95, 97, and 201 [13]

HOVON/SAKK AML- 42 [7]

ECOG1900 [4]

Median age, years

36

46

49

48

Age range, years

15–55

15–64

40–55

50–64

17–60

17–60

CBFβ-MYH11, no.

33

107

15

34

44

57

AML1-ETO, no.

131

408

43

134

44

48

CBFβ-MYH11 in CBF (%)

20.1

20.8

25.9

20.2

50.0

54.3

P value (vs. ECOG1900)

< 0.001

< 0.001

< 0.001

< 0.001

0.553

 

P value (vs. HOVON/SAKK AML- 42)

< 0.001

< 0.001

0.004

< 0.001

 

0.553

aData from our cohort (ChiCTR-TRC-10001202)

All these data indicate that the different incidence of patterns of mutation acquisition exists between Caucasian and Eastern Asian population, suggesting that genetic backgrounds have an impact on leukemogenesis. We think that these differences become more and more important and are needed to be further investigated, since many novel drugs, such as FLT3 and IDH2 inhibitors, target on genetic mutations and the effectiveness may depend on patterns of mutation acquisition.

Abbreviations

AML: 

Acute myeloid leukemia

CBF: 

Core binding factor

MUT: 

Mutant

WT: 

Wild type

Declarations

Acknowledgements

Not applicable.

Funding

This study was supported by State Key Program of National Natural Science Foundation of China (81430004), Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81421002), National Natural Science Foundation of China (81670159), and CAMS Innovation Fund for Medical Sciences (CIFMS 2016-I2M-1-001, 2016-I2M-3-004).

Availability of data and materials

The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

Hui Wei and JianxiangWang designed and performed the experiments, analyzed the data, and wrote the paper. Yingchang Mi provided comments on writing the paper. All authors contributed to the interpretation of the results. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The data about the patients were used after obtaining approval by the ethical committee of Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Leukemia Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
(2)
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People’s Republic of China

References

  1. Lee JH, Joo YD, Kim H, Bae SH, Kim MK, Zang DY, Lee JL, Lee GW, Lee JH, ParkJH, Kim DY, Lee WS, Ryoo HM, Hyun MS, Kim HJ, Min YJ, Jang YE, Lee KH; Cooperative Study Group A for Hematology. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011;118(14):3832-3841.Google Scholar
  2. Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011;117(8):2358–65.View ArticlePubMedGoogle Scholar
  3. Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, Hu JD, Wang JM, Li JY, Huang XJ, Ma J, Ji CY, Xu XP, Yu K, Ren HY, Zhou YH, Tong Y, Lou YJ, Ni WM, Tong HY, Wang HF, Mi YC, Du X, Chen BA, Shen Y, Chen Z, Chen SJ. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: amulticentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013;14(7):599–608.View ArticlePubMedGoogle Scholar
  4. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, Racevskis J, Dewald GW, Ketterling RP, Bennett JM, Rowe JM, Lazarus HM, Tallman MS. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249–59.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol. 2013;31(27):3360–8.View ArticlePubMedGoogle Scholar
  6. Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L, McMullin MF,Cahalin P, Dennis M, Friis L, Thomas IF, Milligan D, Clark RE; UK NCRI AML Study Group. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 2015;125(25):3878-3885.Google Scholar
  7. Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Biemond BJ, Gratwohl A, de Greef GE, Verdonck LF, Schaafsma MR,Gregor M, Theobald M, Schanz U, Maertens J, Ossenkoppele GJ; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011;364(11):1027-1036.Google Scholar
  8. Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, Thiede C, Hänel M, Schäfer-Eckart K, Aulitzky W, Einsele H, Ho AD, Serve H, Berdel WE, Mayer J, Schmitz N, Krause SW, Neubauer A, Baldus CD, Schetelig J, Bornhäuser M, Ehninger G. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013;31(17):2094–102.View ArticlePubMedGoogle Scholar
  9. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.View ArticlePubMedGoogle Scholar
  10. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007;110(4):1262–70.View ArticlePubMedGoogle Scholar
  11. Gale RE, Lamb K, Allen C, El-Sharkawi D, Stowe C, Jenkinson S, Tinsley S, Dickson G, Burnett AK, Hills RK, Linch DC. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33(18):2072–83.View ArticlePubMedGoogle Scholar
  12. Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction withFLT3 and NPM1 mutations. J Clin Oncol. 2010;28(16):2739–47.View ArticlePubMedGoogle Scholar
  13. Yanada M, Ohtake S, Miyawaki S, Sakamaki H, Sakura T, Maeda T, Miyamura K, Asou N, Oh I, Miyatake J, Kanbayashi H, Takeuchi J, Takahashi M, Dobashi N, Kiyoi H, Miyazaki Y, Emi N, Kobayashi Y, Ohno R, Naoe T; Japan Adult Leukemia Study Group. The demarcation between younger and older acute myeloid leukemia patients: a pooled analysis of 3 prospective studies. Cancer 2013;119(18):3326-3333.Google Scholar

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© The Author(s). 2018

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