Molecular genetic and clinical characterization of acute myeloid leukemia with trisomy 8 as the sole chromosome abnormality

Figures & data

Table 1. Clinical characteristics of AML patients with trisomy 8 as the sole chromosome abnormality.

Case No. /Sex/Age(y)	WBC (×10^9/L)	HB (g/L)	PLT (×10^9/L)	FAB subtype	Induction therapy regimen	Response to induction therapy	Allo-HSCT
1/Female/39	47.57	75	37	M5	DA	NR	No
2/Female/50	174	89	59	M5	DA	NR	No
3/Female/61	13.2	74	44	M5	DA	CR	No
4/Female/49	45.7	60	34	M5	DA	CR	Yes
5/Female/44	87	49	18	M5	DA	CR	No
6/Female/53	45	75	30	M5	HAD	CR	Yes
7/Female/27	17	62	47	M5	DA	CR	No
8/Male/18	6.2	101	51	M5	HAD	NR	No
9/Male/30	0.61	70	317	M5	Decitabine + CAG	CR	Yes
10/Female/55	5.55	63	389	M2	DA	NR	No
11/Male/37	33	107	104	M5	HAD	CR	No
12/Female/55	0.87	65	5	Unclassified	Decitabine + CAG	CR	No
13/Male/63	46.38	69	74	M4	IA	NR	No
14/Male/71	4.65	68	34	M1	DAC	NR	No
15/Female/64	2.92	92	49	M5	Decitabine + CAG	NR	No
16/Male/61	44.30	73	22	M4	IA	NR	No
17/Female/48	1.91	96	154	Unclassified	Decitabine + IAG	CR	Yes
18/Male/48	2.70	68	32	M4	IA	NR	Yes
19/Male/34	22.35	55	43	Unclassified	Decitabine + IAG	CR	Yes
20/Male/42	139	56	32	Unclassified	IA	NR	Yes
21/Male/23	6.3	92	18	M2	IA	NR	Yes
22/Female/57	3.91	89	84	M1	DA	NR	No
23/Male/25	7.05	39	47	M2	IA	NR	Yes
24/Male/63	1.43	106	58	M1	Decitabine + CAG	CR	No
25/Female/50	0.6	62	29	Unclassified	Decitabine	NR	No
26/Male/55	6.8	63	121	M1	IA	CR	No
27/Male/52	7.8	73	45	M2	IA	CR	Yes
28/Female/30	11	59	40	M1	IA	CR	No
29/Male/64	2.3	83	172	M1	Decitabine	NR	No
30/Female/66	0.79	76	15	Unclassified	Decitabine	NR	No
31/Male/18	11.3	88	46	M2	IA	CR	Yes
32/Male/19	307	116	61	M2	IA	NR	No
33/Male/64	1.24	76	27	M5	Decitabine + CAG	CR	No
34/Female/58	2.39	114	68	M2	Decitabine + CAG	PR	No
35/Female/46	6.86	74	49	M1	IA	PR	No

Abbreviations: AML: acute myeloid leukemia (AML); F: female; M: male; WBC: white blood cell count; HB: hemoglobin; PLT: platelet; DA: daunorubicin cytarabine; IA: idarubicin cytarabine; HAD: Homoharringtonine, cytarabine and daunorubicin; CAG: aclarubicin, cytarabine and G-CSF; IAG: idarubicin, cytarabine and G-CSF; CR: complete remission; NR: non-remission; PR: partial remission; Allo-HSCT: allogeneic hematopoietic stem cell transplantation.

Table 2. Pretreatment clinical characteristics of AML patients with isolated +8 and comparison by different karyotype groups.

Variable	+8	NK AML	P1	CBF AML	P2	KMT2A-r AML	P3
Gender
Male, n (%)	18(51.4%)	27(42.9%)	0.210	35(42.2%)	0.179	20(48.8%)	0.410
Female, n (%)	17(48.6%)	36(57.1%)		48 (57.8%)		21(51.2%)
Age (year)
Median (range)	50(18–71)	44 (13–68)	0.155	37 (16–73)	0.001	38(18–67)	0.009
WBC (×10^9/L)
Median (range)	6.86(0.6–307)	12.36(0.5–278.5)	0.657	18.66 (1.26–156)	0.008	7.5(0.63–256)	0.942
Hb (g/L)
Median (range)	74(39–116)	92.5 (36–140)	0.001	82(40–124)	0.084	79(48–145)	0.154
PLT (×10^9/L)
Median (range)	46(5–389)	57(6–332)	0.440	26(3–161)	0.0002	46(12–169)	0.278
FAB classification
M1, n(%)	7(20%)	6(9.52%)	0.213	0	0.0001	0	0.003
M2, n(%)	7(20%)	20(31.75%)	0.216	48(57.83%)	0.0002	2(4.88%)	0.072
M4, n(%)	3(8.57%)	7(11.11%)	0.691	33(39.76%)	0.001	3(7.32%)	0.084
M5, n(%)	12(34.28%)	13(20.63%)	0.137	2(2.41%)	0.0001	36(87.80%)	0.00001
M6, n(%)	0	1(1.59%)	–	0	–	0	–
Undetermined, n(%)	6(17.14%)	16 (25.40%)	0.348	0	0.0005	0	0.007
CR rate	16(45.7%)	42(66.67%)	0.001	73(87.95)	0.000	3(75.61)	0.00009

Abbreviations: P: p-value, n: number of patients; AML: acute myeloid leukemia; NK AML:normal karyopype; CBF AML: core binding factor AML; KMT2A-r AML: KMT2A -rearrangement AML. P1, the sole + AML vs. NK AML; P2, the sole + AML vs. CBF AML; P3, the sole + AML vs. KMT2A-r AML.

Table 3. Molecular characteristics of AML patients with isolated +8 and comparison by different karyotype groups.

Mutational genes	+8(n = 35)	NK AML(n = 63)	P1	CBF AML(n = 83)	P2	KMT2A-r AML(n = 41)	P3
NPM1, n(%)	6(17.14%)	23(36.51%)	0.289	3(3.61%)	0.001	0	0.592
Signaling pathways, n (%)	14(40%)	28(44.4%)	0.832	71(85.5%)	0.0000	25(60.9%)	0.107
c-KIT, n (%)	2(5.71%)	1(1.58%)	0.256	29 (34.94%)	0.001	1(2.44%)	0.440
NRAS, n (%)	3(8.57%)	10(15.87%)	0.751	29 (34.94%)	0.044	11(26.83%)	0.218
KRAS, n (%)	1(2.86%)	1(1.58%)	0.490	12(14.46%)	0.291	11(26.83%)	0.023
FLT3-ITD, n (%)	10 (28.57%)	17 (26.98%)	0.866	15(18.07%)	0.202	7(17.07%)	0.231
CSF3R, n (%)	0	3(4.76%)	0.555	7(8.43%)	0.198	4(9.76%)	0.289
RELN, n (%)	0	0		7(8.43%)	0.198	0
NOTCH1, n (%)	0	2(3.17%)	1.00	6(7.23%)	0.333	0
NOTCH2, n (%)	2(5.71%)	1(1.58%)	0.193	3(3.61%)	0.327	0	0.140
JAK2, n (%)	0	0		7(8.43%)	0.198	1(2.44%)	1.000
SH2B3, n (%)	2(5.71%)	0	0.078	2(2.41%)	0.228	1(2.44%)	0.552
PTPN11, n (%)	1(2.86%)	4(6.35%)	1.00	3(3.61%)	1.000	4(9.76%)	0.642
Epigenetic regulators, n (%)	19(54.3%)	33(52.4%)	0.856	5(6.0%)	0.0000	7(17.1%)	0.001
TET2, n (%)	4(11.43%)	11(17.46%)	1.00	4(4.82%)	0.082	4(9.76%)	0.465
IDH1, n (%)	4(11.43%)	10(15.87%)	0.287	1(1.2%)	0.051	1(2.44%)	0.363
IDH2, n (%)	8(22.86%)	11(17.46%)	0.157	1(1.2%)	0.0001	1(2.44%)	0.001
DNMT3A, n (%)	13(37.14%)	19(30.16%)	0.507	0	0.0000	3(7.32%)	0.001
Transcription factors, n (%)	18(51.4%)	22(34.9%)	0.135	8(9.6%)	0.0000	6(14.6%)	0.001
ETV6, n (%)	1(2.86%)	2(3.17%)	1.00	0	0.297	0	0.461
RUNX1, n (%)	10(28.57%)	3(4.76%)	0.001	2(2.41%)	0.00001	0	0.00019
GATA2, n (%)	1(2.86%)	7(11.11%)	0.431	0	0.231	2(4.88%)	1.000
SETBP1, n (%)	2(5.71%)	0	0.078	4(4.82%)	0.621	2(4.88%)	0.630
CEBPA, n (%)	5(14.29%)	12(19.05%)	0.781	3(3.61%)	0.035	3(7.32%)	0.459
Spliceosomes, n (%)	3(8.6%)	2(3.2%)	0.345	3(3.6%)	0.263	1(2.4%)	0.233
SRSF2, n (%)	2(5.71%)	1(1.58%)	0.193	0	0.052	0	0.140
SF3B1, n (%)	1(2.86%)	0	0.284	3(3.61%)	1.000	1(2.44%)	1.000
ZRSR2, n (%)	0	1(1.58%)	1.00	0		0
Tumor suppressors, n (%)	7(20%)	7(11.1%)	0.243	12(14.5%)	0.584	1(2.4%)	0.021
TP53, n (%)	2(5.71%)	0	0.078	3(3.61%)	0.327	1(2.44%)	0.552
FAT1, n (%)	2(5.71%)	4(6.35%)	1.00	3(3.61%)	0.327	0	0.140
WT1, n (%)	3(8.57%)	6(9.52%)	0.876	6(7.23%)	0.802	0	0.029
Chromatin modifiers, n (%)	9(25.71%)	12(19.0%)	0.452	9(10.8%)	0.052	5(12.2%)	0.149
ASXL1, n (%)	5(14.29%)	3(4.76%)	0.039	8(9.64%)	0.174	5(12.2%)	0.485
EZH2, n (%)	2(5.71%)	5(7.94%)	1.00	0	0.052	0	0.140
BCOR, n (%)	1(2.86%)	3(4.76%)	1	1(1.2%)	0.507	0	0.461
BCORL1, n (%)	1(2.86%)	3(4.76%)	1.00	0	0.231	0	0.379
Number of mutated genes
1 mutation	2(5.71%)	5(7.94%)	1.00	17(20.48%)	0.046	14(34.15%)	0.004
2 mutation	7(20%)	12(19.05%)	0.909	18(21.69%)	0.838	14(34.15%)	0.169
3 mutation	7(20%)	16(25.39%)	0.546	19(22.89%)	0.729	5(12.20%)	0.352
≥4 mutation	18(51.43%)	25(39.68%)	0.262	29(34.94%)	0.095	4(9.76%)	0.00006
Average number(range)	3.82(0–10)	3.38(0–11)	0.451	3.13(1–11)	0.989	1.83(0–5)	0.035

Abbreviations: P: p-value; n: number of patients; AML: acute myeloid leukemia; NK AML: normal karyopype; CBF AML: core binding factor AML; KMT2A-r AML: KMT2A-rearrangement AML. P1, the sole + AML vs. NK AML; P2, the sole + AML vs. CBF AML; P3, the sole + AML vs. KMT2A-r AML.

Table 4. Clinical characteristics of the common mutations in the sole +8 AML patients.

Variables	Age, years (Median, range)	Male/Female (n/n)	WBC, ×10^9/L (Median, range)	HB, g/L (Median, range)	PLT, ×10^9/L (Median, range)	CR rate(n/n,%)
DNMT3A
Mutated	48(30–71)	4/9	11(0.79–174)	75(49–114)	37(15–154)	5/13(38.46%)
Wild-type	52.5(18–64)	14/8	6.83(0.6–307)	73.5(39–116)	47(5–389)	11/22(50%)
P value	0.075	0.501	0.488	0.397	0.133	0.288
RUNX1
Mutated	56(46–71)	5/5	2.55(0.87–6.86)	78.5(63–114)	63(5–172)	4/10(40%)
Wild-type	44(18–66)	13/12	13.2(0.6–307)	73(39–116)	44(15–389)	12/25(48%)
P values	0.0049	0.903	0.0203	0.774	0.830	0.372
IDH2
Mutated	51(30–66)	3/5	1.39(0.6–7.8)	71.5(62–96)	38.8(5–317)	4/8(50%)
Wild-type	49(18–71)	15/12	11.3(1.24–307)	74(39–116)	47(18–389)	12/27(44.44%)
P values	0.026	0.429	0.039	0.110	0.163	0.761
FLT3-ITD
Mutated	45.5(18–64)	6/4	46.04(2.3–307)	75(56–116)	45.5(30–172)	3/10(30%)
Wild-type	52(18–71)	13/12	5.55(0.6–87)	73(39–114)	46(5–389)	13/25(52%)
P value	0.802	0.372	0.00001	0.833	0.178	0.047
IDH1
Mutated	52(39–63)	1/3	4.63(1.43–47.57)	90.5(74–114)	53.5(37–68)	1/4(25%)
Wild-type	50(18–71)	17/14	14.1(0.6–307)	73(39–116)	45(5–389)	15/31(48.39%)
P value	0.304	0.015	0.375	0.453	0.188	0.005
CEBPA
Mutated	30(18–55)	2/3	6.2(0.61–174)	70(62–101)	59(47–389)	2/5(40%)
Wild-type	51(18–71)	16/14	6.96(0.6–307)	74(39–116)	43.5(5–172)	14/30(46.67%)
P value	0.761	0.463	0.434	0.971	0.001	0.286
ASXL1
Mutated	48(25–64)	2/3	2.92(0.6–22.35)	62(39–96)	47(29–154)	2/5(40%)
Wild-type	51(18–71)	16/14	7.33(0.61–307)	74(49–116)	45.5(5–389)	14/30(46.67%)
P value	0.767	0.463	0.144	0.207	0.627	0.286
TET2
Mutated	40.5(30–52)	3/1	20.4(0.61–87)	71.5(49–107)	74.5(18–317)	4/4(100%)
Wild-type	50(18–71)	15/16	6.8(0.6–307)	74(39–116)	46(5–389)	12/31(38.71%)
P value	0.206	0.015	0.694	0.765	0.076	0.00011
WT1
Mutated	55(39–63)	1/2	46.38(0.87–47.57)	69(65–75)	37(5–74)	1/3(33.33%)
Wild-type	49.5(18–71)	15/17	6.83(0.6–307)	74(39–116)	46.5(15–389)	15/32(46.88%)
P value	0.409	0.125	0.543	0.071	0.454	0.125

Abbreviations: WBC, white blood cell count; HB, hemoglobin; PLT, platelet count; No., Number; CR, complete remission.

Figure 1. Landscape of mutated genes in acute myeloid Leukemia with trisomy 8 as the sole chromosome abnormality. (A) Distribution of acquired mutations into functional categories.(B)Frequency of gene mutations in sole +8 AML and NK AML. Each bar represents a distinct mutated gene. (C) Spectrum of mutated genes in sole +8 AML divided into different mutational categories; each column represents one sample sequenced here.

Figure 2. Kaplan–Meier estimates of overall survival (OS) according to gene status, age, WBC and treatment (allo-HSCT or not).

Figure 3. Kaplan–Meier estimates of disease-free survival (DFS) according to gene status, age, WBC and treatment (allo-HSCT or not).

Table 5. Univariate and multivariate COX analysis of factors predicting for OS and DFS.

	Overall Survival(OS)						Disease-Free Survival (DFS)
Variable	Univariate			Multivariate			Univariate
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Without Allo-SCT	7.39	2.05–26.04	0.002	9.24	2.45–34.85	0.001	4.79	1.69–13.57	0.003
Age≧60years	1.06	0.31–3.69	0.922				1.22	0.41–3.65	0.727
WBC≥20×10^9/l	1.60	0.60–4.28	0.348				1.54	0.61–3.87	0.357
DNMT3A muted	1.11	0.41–3.00	0.845				1.47	0.59–3.65	0.411
RUNX1 muted	1.48	0.55–3.97	0.440				1.07	0.39–2.95	0.898
FLT3-TD muted	2.48	0.97–6.31	0.058	3.39	1.28–8.98	0.014	2.04	0.81–5.16	0.132
IDH2 muted	0.60	0.17–0.28	0.420				0.54	0.16–1.84	0.324
ASXL1 muted	0.58	0.13–2.54	0.469				0.44	0.10–1.91	0.274

Abbreviations: P: p-value; OS: overall survival; DFS: disease-free survival.

Data availability statement

All data generated or analysed during this study are included in this article or its supplementary material files. Further enquiries can be directed to the corresponding author.