Background
Methods
Patients
SNPs selection and genotyping
SNP | Gene | Position | MAF | Alleles | Region | eQTL P |
---|---|---|---|---|---|---|
rs7543016 |
CMPK1
| 1:47333967 | 0.467 | C/G | Gly8Arg | 0.3 |
rs3760468 |
NME1
| 17:51153130 | 0.376 | A/T | Promoter | 2.3e−21 |
rs2302254 |
NME1
| 17:51153539 | 0.087 | C/T | Promoter | 2.7e−13 |
rs3744660 |
NME2
| 17:51168540 | 0.162 | A/G | Intron | 2.5e−12 |
rs6102991 |
SAMHD1
| 20:36956238 | 0.386 | A/G | Promoter | 2.0e−6 |
rs28372906 |
SAMHD1
| 20:36951753 | 0.063 | C/T | 5′-UTR | NA |
rs6029941 |
SAMHD1
| 20:36891027 | 0.447 | A/G | 3′-UTR | 2.1e−8 |
rs3213150 |
E2F1
| 20:33687284 | 0.357 | C/T | Intron | NA |
rs3213180 |
E2F1
| 20:33675818 | 0.286 | C/G | 3′-UTR | NA |
rs2412344 |
RRM1
| 11:4086354 | 0.430 | C/T | Promoter | 1.1e−6 |
rs183484 |
RRM1
| 11:4119902 | 0.381 | G/T | Arg284Arg | 9.4e−6 |
rs1130609 |
RRM2
| 2:10122793 | 0.343 | G/T | 5′-UTR/Ser59Ala | 1.2e−7 |
Statistical analysis
Results
Baseline characteristics and the overall CR status of the AML patients
Characteristics | Totality, n (%) | Median (range) |
---|---|---|
Gender | 361 | |
Male | 196 (54.3%) | |
Female | 165 (45.7%) | |
Age | 361 | 43 (16–76) years |
FAB classification | ||
M1 | 19 (5.3%) | |
M2 | 193 (53.5%) | |
M4 | 63 (17.5%) | |
M5 | 75 (20.8%) | |
M6 | 6 (1.7%) | |
Undefined | 5 (1.4%) | |
WBC | 356 (98.6%) | 14.7 (0.4–426.0), × 109/L |
LDH | 341 (94.5%) | 363 (17–5853), U/L |
BM blast % | 348 (96.4%) | 71% (17–99%) |
RBC | 356 (98.6%) | 2.19 (0.67–4.98), × 1012/L |
Hemoglobin | 356 (98.6%) | 72 (27–149), g/L |
Platelets | 356 (98.6%) | 34 (2–546), × 109/L |
Neutrophil | 356 (98.6%) | 2.2 (0.0–340.3), × 109/L |
Risk stratifications | ||
Low risk | 71 (19.7%) | |
Intermediate risk | 187 (51.8%) | |
High risk | 78 (21.6%) | |
Undefined | 25 (6.9%) | |
FLT3-ITD mutation | ||
Positive | 42 (11.6%) | |
Negative | 294 (81.4%) | |
Unknown | 25 (6.9%) | |
NPM1 mutation | ||
Positive | 67 (18.6%) | |
Negative | 269 (74.5%) | |
Unknown | 25 (6.9%) | |
CEBPA mutation | ||
Positive | 50 (13.9%) | |
Negative | 286 (79.2%) | |
Unknown | 25 (6.9%) | |
Karyotype | ||
Normal | 255 (70.6%) | |
Abnormal | 84 (23.3%) | |
Unknown | 22 (6.1%) | |
Allo-HCT | ||
Yes | 64 (17.7%) | |
No | 297 (82.3%) | |
CR after two courses of induction therapy | ||
Yes | 205 (56.8%) | |
No | 120 (33.2%) | |
Not evaluated | 36 (10.0%) | |
Chemotherapy regimens | ||
MA | 125 (34.6%) | |
IA | 86 (23.8%) | |
TA | 47 (13.0%) | |
DA | 31 (8.6%) | |
CAG | 52 (14.4%) | |
Other regimens | 20 (5.5%) |
Comparison of CR rate among genotypes after Ara-C based induction therapy and results of unconditional logistic regression analysis
Genotype | Total (n) | CR, n (%) | Non-CR, n (%) |
P
| OR (95% CI) |
P
a
| OR (95% CI)a |
---|---|---|---|---|---|---|---|
CMPK1 rs7543016 | |||||||
CC | 93 | 57 (61.3%) | 36 (38.7%) | 1.00 (reference) | 1.00 (reference) | ||
GC | 167 | 106 (63.5%) | 61 (36.5%) | 0.727 | 0.911 (0.540–1.537) | 0.921 | 0.970 (0.531–1.772) |
GG | 30 | 23 (76.7%) | 7 (23.3%) | 0.125 | 0.482 (0.188–1.238) | 0.076 | 0.365 (0.120–1.111) |
NME1 rs3760468 | |||||||
AA | 115 | 77 (67.0%) | 38 (33.0%) | 1.00 (reference) | 1.00 (reference) | ||
AT | 154 | 96 (62.3%) | 58 (37.7%) | 0.434 | 1.224 (0.737–2.033) | 0.256 | 1.420 (0.775–2.597) |
TT | 44 | 26 (59.1%) | 18 (40.9%) | 0.353 | 1.403 (0.686–2.869) | 0.465 | 1.359 (0.597–3.096) |
NME1 rs2302254 | |||||||
CC | 186 | 123 (66.1%) | 63 (33.9%) | 1.00 (reference) | 1.00 (reference) | ||
CT | 114 | 65 (57.0%) | 49 (43.0%) | 0.114 | 1.473 (0.912–2.375) | 0.288 | 1.355 (0.775–2.370) |
TT | 19 | 13 (68.4%) | 6 (31.6%) | 0.840 | 0.901 (0.327–2.481) | 0.534 | 0.688 (0.212–2.232) |
NME2 rs3744660 | |||||||
GG | 213 | 146 (68.5%) | 67 (31.5%) | 1.00 (reference) | 1.00 (reference) | ||
AG | 89 | 48 (53.9%) | 41 (46.1%) | 0.016 | 1.861 (1.121–3.091) | 0.024 | 1.953 (1.092–3.484) |
AA | 14 | 8 (57.1%) | 6 (42.9%) | 0.376 | 1.634 (0.545–4.897) | 0.770 | 1.299 (0.361–4.673) |
AA+AG | 103 | 56 (54.4%) | 47 (45.6%) | 0.014 | 1.829 (1.127–2.967) | 0.030 | 1.852 (1.062–3.236) |
SAMHD1 rs6102991 | |||||||
AA | 88 | 49 (55.7%) | 39 (44.3%) | 1.00 (reference) | 1.00 (reference) | ||
GA | 161 | 107 (66.5%) | 54 (33.5%) | 0.093 | 0.634 (0.372–1.080) | 0.183 | 0.669 (0.370–1.209) |
GG | 62 | 43 (69.4%) | 19 (30.6%) | 0.090 | 0.555 (0.280–1.101) | 0.063 | 0.483 (0.224–1.038) |
AG+GG | 223 | 150 (67.3%) | 73 (32.7%) | 0.055 | 0.611 (0.369–1.013) | 0.086 | 0.611 (0.349–1.071) |
SAMHD1 rs28372906 | |||||||
TT | 284 | 180 (63.4%) | 104 (36.6%) | 1.00 (reference) | 1.00 (reference) | ||
CT | 32 | 21 (65.6%) | 11 (34.4%) | 0.802 | 0.907 (0.420–1.955) | 0.878 | 0.935 (0.394–2.217) |
CC | 4 | 3 (75.0%) | 1 (25.0%) | 0.632 | 0.577 (0.059–5.618) | 0.953 | 0.933 (0.091–9.524) |
SAMHD1 rs6029941 | |||||||
GG | 88 | 50 (56.8%) | 38 (43.2%) | 1.00 (reference) | 1.00 (reference) | ||
GA | 161 | 107 (66.5%) | 54 (33.5%) | 0.132 | 0.664 (0.389–1.132) | 0.339 | 0.739 (0.398–1.374) |
AA | 65 | 42 (64.6%) | 23 (35.4%) | 0.330 | 0.721 (0.372–1.395) | 0.370 | 0.706 (0.330–1.512) |
E2F1 rs3213180 | |||||||
GG | 149 | 95 (63.8%) | 54 (36.2%) | 1.00 (reference) | 1.00 (reference) | ||
GC | 141 | 90 (63.8%) | 51 (36.2%) | 0.990 | 0.997 (0.617–1.610) | 0.915 | 0.970 (0.552–1.704) |
CC | 29 | 16 (55.2%) | 13 (44.8%) | 0.383 | 1.429 (0.639–3.195) | 0.429 | 1.449 (0.578–3.636) |
E2F1 rs3213150 | |||||||
CC | 111 | 67 (60.4%) | 44 (39.6%) | 1.00 (reference) | 1.00 (reference) | ||
CT | 159 | 110 (69.2%) | 49 (30.8%) | 0.133 | 0.678 (0.408–1.127) | 0.105 | 0.616 (0.343–1.106) |
TT | 46 | 23 (50.0%) | 23 (50.0%) | 0.232 | 1.523 (0.762–3.042) | 0.128 | 1.835 (0.839–4.016) |
CC+CT | 270 | 177 (65.6%) | 93 (34.4%) | 1.00 (reference) | 1.00 (reference) | ||
TT | 46 | 23 (50.0%) | 23 (50.0%) | 0.043 | 1.903 (1.014–3.574) | 0.033 | 2.208 (1.065–4.567) |
RRM1 rs183484 | |||||||
GG | 100 | 62 (62.0%) | 38 (38.0%) | 1.00 (reference) | 1.00 (reference) | ||
GT | 177 | 118 (66.7%) | 59 (33.3%) | 0.434 | 0.816 (0.490–1.359) | 0.112 | 0.617 (0.340–1.119) |
TT | 42 | 22 (52.4%) | 20 (47.6%) | 0.287 | 1.483 (0.716–3.071) | 0.263 | 1.616 (0.697–3.731) |
RRM1 rs2412344 | |||||||
TT | 89 | 56 (62.9%) | 33 (37.1%) | 1.00 (reference) | 1.00 (reference) | ||
CT | 183 | 119 (65.0%) | 64 (35.0%) | 0.734 | 0.913 (0.539–1.545) | 0.510 | 0.817 (0.449–1.488) |
CC | 48 | 28 (58.3%) | 20 (41.7%) | 0.599 | 1.212 (0.592–2.483) | 0.967 | 1.018 (0.429–2.415) |
RRM2 rs1130609 | |||||||
TT | 131 | 84 (64.1%) | 47 (35.9%) | 1.00 (reference) | 1.00 (reference) | ||
GT | 149 | 100 (67.1%) | 49 (32.9%) | 0.599 | 0.876 (0.534–1.436) | 0.920 | 0.972 (0.557–1.697) |
GG | 34 | 15 (44.1%) | 19 (55.9%) | 0.034 | 2.264 (1.053–4.867) | 0.069 | 2.347 (0.935–5.882) |
TT+GT | 280 | 184 (65.7%) | 96 (34.3%) | 1.00 (reference) | 1.00 (reference) | ||
GG | 34 | 15 (44.1%) | 19 (55.9%) | 0.014 | 2.428 (1.181–4.990) | 0.044 | 2.398 (1.025–5.618) |
Combined influence of E2F1 and RRM2 polymorphisms on chemosensitivity to Ara-C based induction therapy in AML patients
rs1130609 | rs3213150 | CR, n (%) | Non-CR, n (%) |
P
| OR (95% CI) |
P
b
| OR (95% CI)b |
---|---|---|---|---|---|---|---|
TT+GT | CC+CT | 158 (66.7%) | 79 (33.3%) | 1.00 (reference) | 1.00 (reference) | ||
TT+GT | TT | 20 (54.1%) | 17 (45.9%) | 0.134 | 1.700 (0.844–3.426) | 0.048 | 2.115 (1.006–4.450) |
GG | CC+CT | 13 (48.1%) | 14 (51.9%) | 0.056 | 2.154 (0.966–4.802) | 0.159 | 1.840 (0.787–4.301) |
GG | TT | 1 (16.7%) | 5 (83.3%) | 0.004 | 10.00 (1.149–87.06) | 0.041 | 9.780 (1.099–87.069) |
Unfavorable combinationsa | 34 (48.6%) | 36 (51.4%) | 0.006 | 2.118 (1.233–3.637) | 0.005 | 2.257 (1.273–4.002) |
Influence of candidate SNPs on RFS and OS for AML patients
Genotype | n | Mean ± SE (day) | Median (range, day) | HR (95% CI) |
P
| HR (95% CI)a |
P
a
|
---|---|---|---|---|---|---|---|
NME1 rs3760468 | |||||||
AA | 113 | 1058 ± 202 | 751 (294–1208) | 1.00 (reference) | 1.00 (reference) | ||
AT | 121 | 1163 ± 212 | 894 (378–1410) | 0.946 (0.657–1.362) | 0.764 | 1.027 (0.709–1.488) | 0.887 |
TT | 39 | 655 ± 207 | 357 (285–429) | 1.703 (1.070–2.709) | 0.025 | 1.744 (1.085–2.801) | 0.022 |
AA+AT | 234 | 1110 ± 149 | 761 (379–1143) | 1.00 (reference) | 1.00 (reference) | ||
TT | 39 | 655 ± 207 | 357 (285–429) | 1.752 (1.142–2.686) | 0.009 | 1.854 (1.197–2.871) | 0.006 |
NME1 rs2302254 | |||||||
CC | 169 | 941 ± 129 | 724 (4484–964) | 1.00 (reference) | 1.00 (reference) | ||
CT | 87 | 1324 ± 266 | 1282 (516–2048) | 0.770 (0.526–1.126) | 0.177 | 0.728 (0.494–1.071) | 0.107 |
TT | 22 | 581 ± 253 | 373 (286–460) | 1.756 (1.014–3.042) | 0.044 | 1.688 (0.973–2.928) | 0.062 |
CC+CT | 256 | 1111 ± 156 | 760 (398–1122) | 1.00 (reference) | 1.00 (reference) | ||
TT | 22 | 581 ± 253 | 373 (286–460) | 1.912 (1.117–3.272) | 0.016 | 1.878 (1.096–3.217) | 0.022 |
NME2 rs3744660 | |||||||
GG | 191 | 987 ± 124 | 751 (397–1105) | 1.00 (reference) | 1.00 (reference) | ||
AG | 71 | 1239 ± 283 | 976 (186–1766) | 0.929 (0.627–1.377) | 0.714 | 0.958 (0.644–1.425) | 0.832 |
AA | 12 | 382 ± 116 | 373 (95–651) | 2.087 (1.051–4.145) | 0.036 | 2.224 (1.114–4.444) | 0.024 |
GG+AG | 262 | 1136 ± 157 | 760 (399–1121) | 1.00 (reference) | 1.00 (reference) | ||
AA | 12 | 382 ± 116 | 373 (95–651) | 2.127 (1.078–4.194) | 0.026 | 2.250 (1.135–4.460) | 0.020 |
RRM2 rs1130609 | |||||||
TT | 123 | 1126 ± 208 | 751 (368–1134) | 1.00 (reference) | 1.00 (reference) | ||
GT | 125 | 1129 ± 216 | 724 (209–1239) | 1.561 (0.692–1.386) | 0.907 | 0.926 (0.651–1.317) | 0.668 |
GG | 29 | 679 ± 272 | 371 (200–542) | 1.561 (0.900–2.707) | 0.113 | 1.437 (0.825–2.501) | 0.200 |
TT+GT | 248 | 1127 ± 159 | 729 (381–1077) | 1.00 (reference) | 1.00 (reference) | ||
GG | 29 | 679 ± 272 | 371 (200–542) | 1.577 (0.935–2.660) | 0.085 | 1.493 (0.882–2.528) | 0.136 |
Genotype | n | Mean ± SE (day) | Median (range) (day) | HR (95% CI) |
P
| HR (95% CI)a |
P
a
|
---|---|---|---|---|---|---|---|
NME1 rs3760468 | |||||||
AA | 135 | 1326 ± 209 | 1534 (947–2121) | 1.00 (reference) | 1.00 (reference) | ||
AT | 160 | 1232 ± 218 | 768 (388–1148) | 1.238 (0.890–1.724) | 0.205 | 1.455 (1.015–2.087) | 0.041 |
TT | 47 | 801 ± 231 | 513 (398–638) | 1.652 (1.067–2.557) | 0.024 | 1.702 (1.072–2.704) | 0.024 |
AT+TT | 207 | 1159 ± 185 | 663 (442–884) | 1.328 (0.973–1.812) | 0.073 | 1.518 (1.082–2.129) | 0.016 |
NME2 rs3744660 | |||||||
GG | 230 | 1283 ± 168 | 1159 (615–1703) | 1.00 (reference) | 1.00 (reference) | ||
AG | 98 | 1175 ± 252 | 817 (410–1224) | 1.283 (0.924–1.780) | 0.137 | 1.181 (0.831–1.679) | 0.353 |
AA | 15 | 442 ± 149 | 359 (167–551) | 2.214 (1.154–4.247) | 0.017 | 2.284 (1.145–4.559) | 0.019 |
GG+AG | 328 | 1261 ± 143 | 988 (682–1294) | 1.00 (reference) | 1.00 (reference) | ||
AA | 15 | 442 ± 149 | 359 (167–511) | 2.054 (1.080–3.905) | 0.025 | 2.172 (1.098–4.294) | 0.026 |
RRM1 rs183484 | |||||||
GG | 109 | 940 ± 167 | 672 (454–890) | 1.00 (reference) | 1.00 (reference) | ||
GT | 194 | 1506 ± 202 | 1749 (799–2699) | 0.692 (0.496–0.964) | 0.030 | 0.599 (0.413–0.868) | 0.007 |
TT | 46 | 993 ± 305 | 414 (162–666) | 1.112 (0.717–1.726) | 0.635 | 1.063 (0.665–1.698) | 0.799 |
RRM2 rs1130609 | |||||||
TT | 148 | 1243 \± 201 | 1025 (426–1624) | 1.00 (reference) | 1.00 (reference) | ||
GT | 161 | 1380 ± 209 | 843 (520–1166) | 0.988 (0.719–1.357) | 0.941 | 1.025 (0.746–1.408) | 0.881 |
GG | 36 | 753 ± 248 | 473 (137–809) | 1.506 (0.917–2.475) | 0.106 | 1.489 (0.906–2.448) | 0.116 |
TT+GT | 309 | 1297 ± 153 | 935 (645–1225) | 1.00 (reference) | 1.00 (reference) | ||
GG | 36 | 753 ± 248 | 473 (137–809) | 1.516 (0.948–2.422) | 0.080 | 1.471 (0.920–2.352) | 0.107 |