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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.
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:
Clinical and genetic characteristics of the AML and MDS groups are listed in Table 1.
Table 1. Clinical features and cytogenetic characteristics of patients with DM-positive AML and MDS*
Characteristic |
DM-positive AML |
DM-positive MDS |
---|---|---|
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. |
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.
Table 2. Correlation of DM with age, cytogenetics, and TP53 abnormalities in AML-MRC and MDS-RAEB*
Parameter |
DM-positive AML-MRC |
DM-negative AML-MRC |
p value |
DM-positive MDS-RAEB |
DM-negative MDS-RAEB |
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. |
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.
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