Comprehensive DNA repair gene expression analysis and its prognostic significance in acute myeloid leukemia

Figures & data

Table 1. Baseline characteristics of AML patients in The Cancer Genome Atlas AML cohort (TCGA-LAML) and the Ewha study group.

Variable	TCGA-LAML		Ewha Study Group
	No. of Patients (N=170)	%	No. of Patients (N=81)	%
Age, years
Median (range)	58 (18–88)		57 (1–99)
Sex (male:female)	92:78	54:46	44:37	54:46
Therapy-related
Yes	NA	NA	7	9
No	NA	NA	74	91
WBC, ×10^9/L
Median (range)	17.0 (1.0–297.0)		8.4 (0.3–453.6)
Hemoglobin, g/dL
Median (range)	9.0 (6.0–14.0)		8.1 (2.4–13.4)
Platelet, ×10^9/L
Median (range)	49 (8–351)		47 (4–1510)
Bone marrow blast, %
Median (range)	36.0 (0.0–98.0)		72.0 (20.0–98.4)
Risk group
APL	15	9	9	11
Non-APL	150	91	72	89
Favorable risk	17	10	27	38
CBF-AML	17	100	14	52
Normal karyotype*	0	0	13	48
Intermediate risk	101	59	31	43
KMT2A (t(9;11))	1	1	2	7
Normal karyotype†	80	80	15	48
Others‡	20	20	14	45
Adverse risk	37	31	14	19
KMT2A	3	8	3	22
Normal karyotype^§	0	0	2	14
Others^¶	12	32	2	14
Complex **	22	60	7	50
Underwent allo-HSCT (N=66)
Yes	NA	NA	10	15
No	NA	NA	56	85

†Normal karyotype with wild-type NPM1 without FLT3-ITD or with FLT3-ITD^low.

‡ Others karyotype except for normal karyotype and t(9;11).

^§ Normal karyotype with wild-type NPM1 and FLT3-ITD^high.

^¶ Others karyotype with del(5q), monosomy 7, del(7q), or t(9;22).

**Complex karyotype was defined as the karyotype with 3 or more chromosomal abnormalities.

Abbreviations; NA: not applicable; Allo-HSCT: allogeneic stem cell transplantation; APL: acute promyelocytic leukemia; CBF: core-binding factor; NK: normal karyotype.

Figure 1. Relative gene expression of DNA repair genes between APL and non-APL AML, (A) percentage of GAPDH as a comparator using RNA-expression profiling on the Affymetrix U133 Plus 2 platform in The Cancer Genome Atlas AML cohort (TCGA-LAML), and (B) fold changes compared to normal controls using quantitative PCR with an RT² Profiler PCR array system in the Ewha study group. The horizontal bars represent medians, boxes represent inter-quartile ranges, and dotted lines represent 5th and 95th percentiles. Abbreviations: APL, acute promyelocytic leukemia.

Figure 2. Relative gene expression of RAD23A, RAD23B, FEN1, and XRCC1 DNA repair gene in non-APL AML risk subgroups (A) using the TCGA-LAML cohort and (B) the Ewha study group. Post-hoc comparison was performed among risk groups. The horizontal bars represent medians, boxes represent inter-quartile ranges, and dotted lines represent 5th and 95th percentiles.

Figure 3. Overall survival of non-APL AML patients (A) according to PARP1, XRCC1, RAD51, and RAD23A in the TCGA cohort and (B) PARP1, XRCC1, RAD51, BRCA1 and MRE11A expression in the Ewha study group by Kaplan Meier log rank test.

Table 2. Multivariate analysis on overall survival of DNA repair genes in non-APL AML patients in the Ewha study group.

Variable		HR	95% CI	P
PARP1	>0.4 Z score	2.53	1.27–5.05	0.0082
Age*		1.03	1.00–1.05	0.0090
Intermediate risk group		2.61†	1.18–5.75	0.0175
Adverse risk group		2.36^†	0.88–6.30	0.0856
Underwent allo-HSCT		0.21	0.06–0.77	0.0180
BRCA1	>1.5 Z score	6.07	1.51–24.31	0.0109
Age*		1.03	1.00–1.05	0.0179
Intermediate risk group		3.13^†	3.13–7.41	0.0096
Adverse risk group		4.20^†	1.51–11.70	0.0061
Underwent allo-HSCT		0.23	0.06–0.82	0.0231
XRCC1	>1.5 Z score	4.12	1.35–12.56	0.0129
Age*		1.03	1.00–1.05	0.0165
Intermediate risk group		2.45^†	1.12–5.38	0.0244
Adverse risk group		3.41^†	1.31–8.82	0.0116
Underwent allo-HSCT		0.25	0.07–0.88	0.0311
RAD51	>1.2 Z score	3.23	1.15–9.08	0.0258
Age*		1.03	1.00–1.05	0.0278
Intermediate risk group		2.42^†	1.11–5.29	0.0271
Adverse risk group		3.06^†	1.18–7.90	0.0211
Underwent allo-HSCT		0.25	0.07–0.88	0.0315
MRE11A	>1.5 Z score	3.10	1.00–9.55	0.0491
Age*		1.03	1.00–1.05	0.0273
Intermediate risk group		2.49^†	1.13–5.46	0.0230
Adverse risk group		3.03^†	1.77–7.82	0.0216
Underwent allo-HSCT		0.24	0.07–0.87	0.0291

Abbreviations: HR: hazard ratio; allo-HSCT: allogeneic hematopoietic stem cell transplantation.

*Continuous variable.

^† Hazard ratio derived by using favorable group as reference category.

Figure 4. Kaplan Meier survival curves of (A) according to the risk groups among all AML patients, and (B) based on the expression levels of DNA repair genes among non-APL AML patients in the Ewha study group. * Patients with at least one gene or more showing Z-scores greater than 1.5. ^† The remaining patients. Abbreviations: APL, acute promyelocytic leukemia.

Table 3. Outcomes of non-APL AML according to the AML risk group and DNA damage response Expression group in the Ewha study group.

Non-APL AML subgroup (N=72)	Early death rate (N=66)		CR rate (N=51)		Relapse rate (N=33)
	N* (%)	P	N* (%)	P	N* (%)	P
AML risk group
Favorable (N=38)	3/25 (12)	0.3322	20/22 (91)	0.0222	8/19 (42)	0.1646
Intermediate (N=43)	8/28 (29)		14/20 (70)		1/10 (10)
Adverse (N=19)	3/13 (23)		4/9 (44)		2/4 (50)
DDR expression group
DDR non-overexpressed (N=39)	2/35 (6)	0.0012	27/32 (84)	0.0378	8/24 (33.3)	1.0
DDR overexpressed (N=33)	12/31 (39)		11/19 (58)		3/9 (33.3)

*The number of patients with the event/the number of patients who were followed up.

Abbreviations: APL: acute promyelocytic leukemia; CR: complete remission; DDR: DNA damage response.

Data availability statement

The TCGA-LAML datasets analyzed for this study can be found in the GDC data portal (https://portal.gdc.cancer.gov). The datasets generated and analyzed of Ewha study group are not publicly available.