Background
Methods
Study population
Chemotherapy regimens
Evaluation of chemotherapy response and toxicity
Identification and selection of poly-miRTS
Gene | SNP ID | Chromosome location | Positiona
| Variants | MAF in CHB | Putative miRNA and effectb
|
---|---|---|---|---|---|---|
SLC29A1
| rs3734703 | 6 | 44233997 | C>A | 0.20 | hsa-miR-1207-5p (break) hsa-miR-571 (decrease) |
NT5C2
| rs10786736 | 10 | 103089359 | G>C | 0.22 | hsa-miR-581 (break) hsa-miR-1238 (enhance) hsa-miR-1236 (decrease) |
rs8139 | 10 | 103088366 | T>C | 0.50 | hsa-miR-373 (break) hsa-miR-578 (break) hsa-miR-125a-3p (create) | |
rs12573199 | 10 | 103089087 | A>T | 0.08 | hsa-miR-325 (create) hsa-miR-548a-5p (break) | |
DCTD
| rs3811810 | 4 | 182890990 | G>A | 0.08 | hsa-miR-574-5p (create) hsa-miR-599 (create) |
rs7278 | 4 | 182890334 | C>T | 0.17 | hsa-miR-935 (decrease) | |
rs851
| 4 | 182890517 | G>A | 0.30 | hsa-miR-1288 (create) hsa-miR-423-5p (enhance) hsa-miR-556-5p (create) | |
rs9542 | 4 | 182891198 | G>A | 0.47 | hsa-miR-1305 (break) | |
RRM1
| rs1042919 | 11 | 4138534 | T>A | 0.32 | hsa-miR-944 (enhance) |
SLC28A1
| rs8025045 | 15 | 84945341 | G>T | 0.06 | hsa-miR-500 (create) hsa-miR-574-3p (decrease) hsa-miR-767-3p (decrease) |
CBR1
| rs9024 | 21 | 36073015 | G>A | 0.20 | hsa-miR-944 (break) hsa-miR-325 (enhance) |
ABCB1
| rs3842 | 7 | 87504050 | A>G | 0.28 | hsa-miR-548g (break) |
ABCC1
| rs212090 | 16 | 16142147 | T>A | 0.14 | hsa-miR-1292 (break) hsa-miR-548j (break) hsa-miR-450b-3p (create) hsa-miR-769-3p (create) hsa-miR-199a-3p (decrease) hsa-miR-199b-3p (decrease) |
rs212091 | 16 | 16142793 | A>G | 0.26 | hsa-miR-1303 (create) | |
rs3743527 | 16 | 16141824 | C>T | 0.45 | hsa-miR-625 (break) hsa-miR-141 (break) hsa-miR-760 (break) hsa-miR-1291 (enhance) | |
rs4148380 | 16 | 16142574 | G>A | 0.05 | hsa-miR-187 (break) hsa-miR-599 (create) | |
NQO1
| rs10517 | 16 | 69709857 | C>T | 0.37 | hsa-miR-1243 (create) hsa-miR-587 (create) hsa-miR-324-5p (enhance) |
Genotyping
Statistical analysis
Results
Patient characteristics and treatment outcomes
Characteristics | Patients, n (%) | Median (range) |
---|---|---|
Sex | ||
Male | 101 (49.0) | |
Female | 105 (51.0) | |
Age at diagnosis, year | 43 (13–76) | |
≥ 43 | 106 (51.5) | |
< 43 | 100 (48.5) | |
BM blasts, % | 67.2 (22–97.8) | |
≥ 67.2 | 100 (48.5) | |
< 67.2 | 99 (48.1) | |
Unknown | 7 (3.4) | |
WBC, ×109/L | 20.7 (0.29–412.5) | |
≥ 20.7 | 104 (50.5) | |
< 20.7 | 102 (49.5) | |
Hemoglobin, g/L | 81 (20–138) | |
≥ 81 | 103 (50.0) | |
< 81 | 101 (49.0) | |
Unknown | 2 (1.0) | |
Platelets, ×109/L | 206 | 38.5 (5–542) |
< 38.5 | 103 (50) | |
≥ 38.5 | 103 (50) | |
FAB classification | ||
M0 | 2 (1.0) | |
M1 | 14 (6.8) | |
M2 | 104 (50.5) | |
M4 | 31 (15.0) | |
M5 | 46 (22.3) | |
M6 | 7 (3.4) | |
M7 | 2 (1.0) | |
Risk stratificationsa
| ||
Low risk | 35 (17.0) | |
Intermediate risk | 118 (57.3) | |
High risk | 53 (25.7) | |
FLT3-ITD mutation | ||
Positive/negative | 25/181 (12.1/87.9) | |
NPM1 mutation | ||
Positive/negative | 32/174 (15.5/84.5) | |
KIT mutation | ||
Positive/negative | 9/197 (4.4/95.6) | |
CEBPA mutation | ||
Positive/negative | 7/199 (3.4/96.6) | |
Karyotype | ||
Normal | 133 (64.6) | |
inv (16) | 8 (3.9) | |
t (8;21) | 11 (5.3) | |
t (6;9) | 3 (1.5) | |
t (9;22) | 1 (0.5) | |
t (9;11) | 2 (1.0) | |
inv (3) | 1 (0.5) | |
+ 8 | 2 (1.0) | |
− 7 | 1 (0.5) | |
Other | 44 (21.4) | |
Treatment response | ||
CR | 176 (85.4) | |
CR after 1st course | 125 (60.7) | |
CR after 2nd course | 51 (24.8) | |
Non-CR | 30 (14.6) | |
Treatment outcome | ||
Death | 31 (15.0) | |
Relapse | 21 (10.2) | |
Adverse events (grade ≥ 2) | ||
Myelosuppression | 168 (81.6) | |
Liver function damage | 23 (11.2) | |
Cardiotoxicity | 11 (5.3) | |
Gastrointestinal reaction | 66 (32.0) |
Association between clinical characteristics and chemotherapy response and toxicity, OS, and RFS
Clinical variables | Clinical outcomes |
P
| OR/HR (95% CI) |
---|---|---|---|
Risk stratifications | OS (mean day ± SE) | 0.027 | |
Low + intermediate | 1473 ± 82 | 1.00 (reference) | |
High | 1048 ± 113 | 2.325 (1.103–4.900) | |
Risk stratifications | PFS (mean day ± SE) | 0.013 | |
Low | 1532 ± 151 | 1.00 (reference) | |
Intermediate | 1096 ± 99 | 0.056 | 2.762 (0.974–7.834) |
High | 740 ± 105 | 0.005 | 4.801 (1.606–14.350) |
Platelets, ×109/L | CR (%) | ||
< 38.5 | 78.6 | 1.00 (reference) | |
≥ 38.5 | 92.2 | 0.006 | 3.225 (1.362–7.635) |
Risk stratifications
| Liver function damage (%) | 0.009 | |
Low | 22.9 | 1.00 (reference) | |
Intermediate | 5.9 | 0.008 | 0.213 (0.071–0.638) |
High | 15.1 | 0.355 | 0.660 (0.202–1.784) |
Risk stratifications | Cardiotoxicity (%) | 0.004 | |
Low | 17.1 | 1.00 (reference) | |
Intermediate | 2.5 | 0.005 | 0.126 (0.030–0.535) |
High | 3.8 | 0.079 | 0.190 (0.036–1.001) |
Associations between poly-miRTS and response to chemotherapy
Genotype | Total (N) | CR, N (%) |
P
| OR (95% CI) |
P
a
| OR (95% CI)a
|
---|---|---|---|---|---|---|
rs3811810 | ||||||
GG | 167 | 138 (82.6) | 1.00 (reference) | 1.00 (reference) | ||
AA | 3 | 3 (100) | 0.999 | – | – | |
GA | 36 | 35 (97.2) | 0.054 | 7.355 (0.968–55.873) | 0.070 | 6.671 (0.854–52.098) |
AA+GAb
| 39 | 38 (97.4) | 0.044 | 7.986 (1.053–60.532) | 0.058 | 7.258 (0.934–56.388) |
rs7278 | ||||||
CC | 165 | 136 (82.4) | 1.00 (reference) | 1.00 (reference) | ||
TT | 4 | 4 (100) | 0.999 | – | – | |
TC | 37 | 36 (97.3) | 0.049 | 7.676 (1.011–58.276) | 0.053 | 7.588 (0.971–59.319) |
TT+TCb
| 41 | 40 (97.6) | 0.038 | 8.529 (1.127–64.581) |
0.040
| 8.572 (1.106–66.423) |
rs1042919 | ||||||
TT | 109 | 101 (92.7) | 1.00 (reference) | 1.00 (reference) | ||
AA | 9 | 7 (77.8) | 0.146 | 0.277 (0.049–1.561) | 0.060 | 0.165 (0.025–1.078) |
AT | 88 | 68 (77.3) | 0.003 | 0.269 (0.112–0.646) |
0.003
| 0.253 (0.102–0.630) |
AA+ATb
| 97 | 75 (77.3) | 0.003 | 0.270 (0.114–0.640) |
0.002
| 0.246 (0.100–0.604) |
rs3734703 | ||||||
CC | 122 | 108 (88.5) | 1.00 (reference) | 1.00 (reference) | ||
AA | 17 | 16 (94.1) | 0.495 | 2.074 (0.255–16.863) | 0.495 | 2.097 (0.249–17.630) |
CA | 67 | 52 (77.6) | 0.050 | 0.449 (0.202–1.000) | 0.066 | 0.455 (0.197–1.054) |
CC+AA/CAc
| 139 | 124 (89.2) | 0.030 | 2.385 (1.087–5.231) |
0.023
| 2.561 (1.136–5.775) |
Association between poly-miRTS and chemotherapy toxicity
SNP genotypes | Total (n) | Adverse events | OR (95% CI) | ||
---|---|---|---|---|---|
Yes (n, %) | No (n) | ||||
rs3743527 | Myelosuppression | ||||
CC | 63 | 48 (76.2) | 15 | 1.00 (reference) | |
TC | 108 | 85 (78.7) | 23 | 0.703 | 1.155 (0.51–2.422) |
TT | 35 | 34 (97.1) | 1 |
0.007
| 10.625 (1.339–84.317) |
TC+TTa
| 143 | 119 (83.2) | 24 | 0.236 | 1.549 (0.749–3.206) |
rs212091 | Myelosuppression | ||||
AA | 122 | 107 (87.7) | 15 | 1.00 (reference) | |
AG | 72 | 51 (70.8) | 21 |
0.003
| 0.340 (0.162–0.715) |
GG | 12 | 9 (75.0) | 3 | 0.431 | 0.421 (0.102–1.729) |
AG+GGa
| 84 | 60 (71.4) | 24 |
0.003
| 0.350 (0.171–0.719) |
rs212090 | Gastrointestinal reaction | ||||
TT | 135 | 37 (27.4) | 98 | 1.00 (reference) | |
AT | 63 | 29 (46.0) | 34 |
0.010
| 2.259 (1.211–4.213) |
AA | 8 | 0 (0) | 8 | 0.192 | – |
AA+ATa
| 71 | 29 (40.8) | 42 | 0.049 | 1.829 (0.998–3.35) |
rs9024 | Cardiotoxicity | ||||
GG | 123 | 2 (1.6) | 121 | 1.00 (reference) | |
GA | 69 | 7 (10.1) | 62 |
0.020
| 6.831 (1.378–33.866) |
AA | 14 | 2 (14.3) | 12 | 0.052 | 10.083 (1.301–78.151) |
GA+AAa
| 83 | 9 (10.8) | 74 |
0.010
| 7.358 (1.547–34.989) |
Association between poly-miRTS and survival of AML patients
Genotype | Mean ± SE (day) | P | RR (95% CI) | Pa
| RR (95% CI)a
|
---|---|---|---|---|---|
rs10786736 | |||||
GG | 1134 ± 115 | 1.00 (reference) | 1.00 (reference) | ||
CC | 1367 ± 149 | 0.236 | 0.414 (0.096–1.780) | 0.253 | 0.426 (0.099–1.836) |
CG | 1550 ± 95 | 0.022 | 0.404 (0.186–0.876) |
0.016
| 0.386 (0.177–0.839) |
CC+CGb
| 1560 ± 85 | 0.015 | 0.406 (0.196–0.841) |
0.012
| 0.392 (0.189–0.815) |
GG+CCc
| 1192 ± 107 | 0.045 | 2.178 (1.018–4.660) |
0.033
| 2.297 (1.070–4.933) |
rs3734703 | |||||
CC | 1571 ± 83 | 1.00 (reference) | 1.00 (reference) | ||
AA | 801 ± 146 | 0.001 | 5.121 (1.985–13.214) |
0.000
| 5.877 (2.244–15.39) |
CA | 1290 ± 127 | 0.056 | 2.231 (0.981–5.073) | 0.057 | 2.219 (0.975–5.050) |
AA+CAb
| 1100 ± 133 | 0.006 | 2.842 (1.350–5.980) |
0.005
| 2.902 (1.377–6.117) |
rs8139 | |||||
TT | 1440 ± 137 | 1.00 (reference) | 1.00 (reference) | ||
CC | 1039 ± 166 | 0.042 | 2.538 (1.033–6.236) | 0.060 | 2.370 (0.963–5.831) |
CT | 1526 ± 93 | 0.391 | 0.671 (0.270–1.669) | 0.204 | 0.547 (0.215–1.388) |
CC/CT | 0.002 | 3.782 (1.662–8.607) |
0.001
| 4.334 (1.885–9.964) | |
TT+CTd
| 1510 ± 78 | 0.001 | 3.259 (1.574–6.746) |
0.001
| 3.475 (1.674–7.213) |
Genotype | Mean ± SE (day) |
P
| HR (95% CI) |
P
a
| HR (95% CI)a
|
---|---|---|---|---|---|
rs10786736 | |||||
GG | 925 ± 113 | 1.00 (reference) | 1.00 (reference) | ||
CC | 892 ± 146 | 0.722 | 0.851 (0.350–2.070) | 0.926 | 0.959 (0.393–2.342) |
CG | 1267 ± 10 | 0.032 | 0.523 (0.289–0.946) |
0.026
| 0.507 (0.279–0.921) |
CC+CGb
| 1214 ± 99 | 0.050 | 0.577 (0.333–1.000) |
0.049
| 0.574 (0.331–0.997) |
CC+GGc
| 912 ± 97 | 0.034 | 1.855 (1.047–3.287) |
0.022
| 1.957 (1.101–3.478) |
rs3734703 | |||||
CC | 1325 ± 96 | 1.00 (reference) | 1.00 (reference) | ||
AA | 592 ± 157 | 0.000 | 4.257 (1.936–9.360) |
0.000
| 4.615 (2.086–10.209) |
CA | 921 ± 123 | 0.014 | 2.158 (1.169–3.984) |
0.032
| 1.955 (1.058–3.611) |
AA+CAb
| 815 ± 113 | 0.001 | 2.544 (1.446–4.478) |
0.003
| 2.357 (1.337–4.155) |
rs8139 | |||||
TT | 1088 ± 150 | 1.00 (reference) | 1.00 (reference) | ||
CC | 834 ± 172 | 0.122 | 1.801 (0.855–3.796) | 0.175 | 1.677 (0.794–3.541) |
CT | 1182 ± 100 | 0.482 | 0.789 (0.408–1.526) | 0.249 | 0.673 (0.343–1.319) |
CC/CT | 0.015 | 2.282 (1.174–4.435) |
0.007
| 2.537 (1.295–4.970) | |
TT+CTd
| 1176 ± 86 | 0.018 | 2.105 (1.134–3.907) |
0.015
| 2.172 (1.162–4.059) |
Combined effects of SNPs on chemotherapy response, OS, and RFS
Composite scorea
| N | CR (%) |
P
|
P
b
| OR (95% CI)b
|
---|---|---|---|---|---|
0 | 32 | 68.8 | 1.00 (reference) | ||
1 | 77 | 79.2 | 0.246 | 0.270 | 1.767 (0.642–4.865) |
2 | 79 | 94.9 | 0.001 | 0.001 | 8.604 (2.318–31.93) |
3 | 18 | 100 | 0.998 | 0.998 | – |
1 + 2 + 3 | 174 | 85.4 | 0.005 | 0.008 | 3.624 (1.398–9.395) |