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Double minute chromosomes associated with rare cytogenetic abnormalities and poor prognosis in MDS and AML

Aug 19, 2021
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Double minute chromosomes (DM) are circular extrachromosomal DNA fragments, which can replicate autonomously and carry amplified oncogenes. Although rare in hematologic malignancies, studies have associated DM with worse prognosis and survival in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Little is known about the modus operandi, genetic characteristics, and the extent to which DM affect prognosis in the AML and MDS settings.

Wang and colleagues1 recently published a study in Leukemia & Lymphoma, which analyzed the cytogenetic characteristics and clinical features of patients with AML and MDS harboring DM.1 Here, we summarize the key findings.

Study design

Largest retrospective single-center study performed so far, with a cohort of DM-positive myeloid tumors, with a span of 7 years. A total of 2,576 patients with AML and 1,642 patients with MDS were included. 30 patients (AML = 19, MDS = 11) who had DM abnormalities were identified, followed, and compared with 30 patients with AML-myelodysplasia-related changes (AML-MRC) without DM, and 30 patients with MDS-refractory anemia with excess blasts (MDS-RAEB) who were DM-negative. All patients satisfied the World Health Organization (WHO) classification systems 2016 diagnostic criteria:

  • for the cytogenetic analysis, traditional karyotyping of metaphases was performed
  • fluorescence in situ hybridization (FISH) analysis was used to detect MYC, KMT2A mutations
  • TP53 sequence analysis identified point mutations and corresponding amino acid changes

Results

Clinical features and cytogenetic characteristics

Clinical and genetic characteristics of the AML and MDS groups are listed in Table 1.

  • In the AML group, the frequency of DM was 0.74%; while in the MDS group, the frequency of DM was 0.67%.
  • The adverse group accounted for 84.2% of the AML group, according to the National Comprehensive Cancer Network (NCCN) guidelines (2018). All patients in the MDS group belonged to the high-risk and very high-risk categories, according to the 2012 Revised International Prognostic Scoring System (IPSS-R) and 2011 Revised WHO-based Prognostic Scoring System (WPSS-R).
  • The number of DM in each metaphase changed depending on the patient’s condition.
  • DM were more common in primary AML (94.7%) and MDS (90.9%).
  • Monosomal karyotypes (MK) and complex karyotypes (CK), especially highly complex karyotypes (HCK), were the most frequent cytogenetic characteristics in the AML group (MK: 68.4%, CK: 78.9%) and in the MDS group (MK: 63.6%, CK: 90.9%).
  • AML-MRC (73.7%) and MDS-RAEB (90.9%) were common in the cohort.
  • Marker chromosomes (31.6%), polyploid karyotype (15.8%), and ring chromosomes (10.5%), were also observed in the AML group, but only marker chromosomes (54.5%) were identified in the MDS group.

Table 1. Clinical features and cytogenetic characteristics of patients with DM-positive AML and MDS*

Characteristic

DM-positive AML
(n = 19)

DM-positive MDS
(n = 11)

Sex, female/male

8/11

4/7

Age, years (range)

64 (37–80)

66 (51–89)

≥ 60 years, %

57.9

54.5

Primary AML/MDS, %

94.7

90.9

Incidence of MRC, %

73.7

CK+, %

78.9

90.9

HCK§, %

57.9

72.7

MK+, %

68.4

63.6

Monosomy, %

              20

61.5

              17

46.2

              7

38.5

              8

38.5

              5

42.9

              12

42.9

              17

42.9

              18

42.9

CK+ and MK+, %

68.4

63.6

CK+ and MK−, %

10.5

27.3

5q−/−5, %

47.7

72.7

7q−/−7, %

31.6

54.5

13q−/−13, %

15.8

27.3

del (12p), %

10.5

9.0

del (11q), %

5.3

18.2

20q−/−20, %

36.8

54.5

17p−/−17, %

36.8

54.5

Trisomy 8, %

21.1

9.0

i (17q), %

0.0

9.0

Marker chromosomes, %

31.6

54.5

Polyploid karyotype, %

15.8

0.0

Ring chromosomes, %

10.5

0.0

MYC FISH, %

50.0

11.1

KMT2A FISH, %

12.5

0.0

TP53 del FISH, %

50.0

80.0

TP53 mut, %

81.8

62.5

Adverse group, %

84.2

100.0

1-year survival rate, %

42.1

27.3

3-year survival rate, %

26.3

9.1

AML, acute myeloid leukemia; CK, complex karyotype; del, deletion; DM, double minute chromosomes; HCK, highly complex karyotype; MDS, myelodysplastic syndromes; MK, monosomal karyotype; mut, mutation.
*Data adapted from Wang et al.1
MRC defined as complex aberrant, −7/del(7q), −5/del(5q), i(17q), −13/del(13q), del(11q), del(12p), t(12p), idic(X) (q13), t(11;16), t(3,21), t(1;3), t(2;11), t(5;7), t(5;17), t(5;10), and t(3;5).
CK defined as ≥3 unrelated chromosome abnormalities in the absence of one of the WHO-designated recurring translocations/inversions.
§HCK defined as the presence of ≥5 numerical/structural chromosomal abnormalities.
MK defined as ≥2 autosomal monosomies/1 autosomal monosomy in combination with a structural aberration.

FISH analysis of MYC, KMT2A, TP53 deletion, and TP53 mutation

  • MYC and KMT2A were the most amplified genes in DM.
  • In the AML group (n = 19), 16 patients had sufficient samples for FISH detection of MYC and KMT2A. MYC positivity rate was 50% and 12.5% presented positive of KMT2A.
  • In the MDS group (n = 11), nine patients had sufficient samples for FISH testing. Only one case was positive for MYC, and none of the cases was positive for KMT2A.
  • In the AML group, 12 patients underwent FISH detection of TP53 deletion, and the positivity rate was 50%. All TP53 mutation-positive cases (81.8%) were found in the adverse group, and all TP53 deletion patients (66.7%) in the AML group showed TP53 mutation positivity.
  • In the MDS group, five patients had sufficient samples for FISH detection of TP53 deletion, and the positivity rate was 80%; eight patients were tested for TP53 mutation, and the positivity rate was 62.5%.

Survival and prognosis in AML-MRC and MDS-RAEB patients

Significant selected parameters from a comparative analysis of the relationship between age, cytogenetics, and TP53 abnormalities in AML-MRC and MDS-RAEB patients, are summarized in Table 2.

  • DM-positive AML-MRC patients and DM-positive MDS-RAEB patients were older, with a higher median age (67 years vs 55 years, 65 years vs 48 years, respectively, both p <0.05).

Table 2. Correlation of DM with age, cytogenetics, and TP53 abnormalities in AML-MRC and MDS-RAEB*

Parameter

DM-positive AML-MRC
(n = 14)

DM-negative AML-MRC
(n = 30)

p value

DM-positive MDS-RAEB
(n = 10)

DM-negative MDS-RAEB
(n = 30)

p value

Age (years), median (range)

66.8 (43–80)

54.5 (23–91)

0

65.4 (48–89)

48.0 (18–86)

0

CK, %

92.9

23.3

0

90.0

16.7

0

MK, %

85.7

13.3

0

60.0

16.7

0.025

5q−/−5, %

64.3

16.7

0.005

70.0

13.3

0.002

20q−/−20, %

50.0

6.7

0.004

50.0

6.7

0.008

17p−/−17, %

50.0

10.0

0.010

60.0

0

0

Marker chromosomes, %

35.7

6.7

0.025

60.0

10.0

0.004

TP53 mutation, %

90.0

34.6

0.007

62.5

4.8

0.003

Adverse risk

100.0

50.0

0.004

IPSS-R very-high-risk, %

90.0

30.0

0.003

WPSS very-high-risk, %

70.0

20.0

0.011

AML, acute myeloid leukemia; CK, complex karyotype; DM, double minute chromosomes; IPSS-R, Revised International Prognostic Scoring System; MDS, myelodysplastic syndromes; MK, monosomal karyotype; MRC, myelodysplasia-related changes; RAEB, refractory anemia with excess blasts; WPSS, Revised WHO-based Prognostic Scoring System.
*Data adapted from Wang et al.1

Survival and follow-up

  • In the AML group, the median survival time (MST) was 5 months (95% Cl, 0.000–14.598), the 1-year survival rate was 42.1%, and the 3-year survival rate was 26.3%.
  • The MST of the MDS group was 9 months (95% Cl, 6.411–11.589), the 1-year survival rate was 27.3%, and the 3-year survival rate was 9.1%.
  • DM positive AML-MRC patients had a worse overall survival (OS) rate (median OS: 4 months vs 13 months, p = 0.033) compared to patients with DM-negative AML-MRC. The OS in the DM-positive MDS-RAEB patients was also poor (median OS: 38 months vs 7 months, p = 0.002) compared to patients with DM-negative MDS-RAEB.
  • At the last follow-up, 29/30 patients had died of disease.

Conclusion

This study demonstrates that patients with DM are at risk of inferior outcomes. DM-positive AML-MRC and DM-positive MDS-RAEB are correlated with older age, CK, MK, TP53 mutations, and poor prognosis. Additionally, CK, MK, and HCK were amongst the main cytogenic characteristics in DM-positive AML /MDS, while MYC and KMT2A were the most amplified genes in DM. Limitations of the study include changes in treatment options and lost patient information. Further studies are warranted to determine whether DM could be used as diagnostic markers and treatment targets for myeloid malignancies.

  1. Wang N, Yuan L, Jing Y, et al. Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndromes are associated with complex karyotype, monosomal karyotype, TP53 deletion, and TP53 Leukemia & Lymphoma. 2021;1-9. DOI: 10.1080/10428194.2021.1919663

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