Clinical and hematologic characteristics at diagnosis and outcome of 127 children with JMML according to CpG island methylation at 4 genetic loci (BMP4, CALCA, CDKN2B, and RARB)
| . | Total cohort . | Normal BMP4 methylation . | BMP4 hyper-methylation . | P . | Normal CALCA methylation . | CALCA hyper-methylation . | P . | Normal CDKN2B methylation . | CDKN2B hyper-methylation . | P . | Normal RARB methylation . | RARB hyper-methylation . | P . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 127 | 81 | 46 | 58 | 68 | 99 | 28 | 111 | 16 | ||||
| Median age, years (range) | 1.4 (0.1-12.2) | 1.1 (0.1-7.0) | 3.6 (0.2-12.2) | < .001 | 0.7 (0.1-3.6) | 2.9 (0.2-12.2) | < .001 | 1.2 (0.1-6.6) | 4.0 (0.3-12.2) | < .001 | 1.4 (0.1-12.2) | 3.7 (0.8-6.6) | < .001 |
| Sex | .701 | .710 | > .999 | .787 | |||||||||
| Male | 82 (65%) | 51 (63%) | 31 (67%) | 36 (62%) | 45 (66%) | 64 (65%) | 18 (64%) | 71 (64%) | 11 (69%) | ||||
| Female | 45 (35%) | 30 (37%) | 15 (33%) | 22(38%) | 23 (34%) | 35 (35%) | 10 (36%) | 40 (36%) | 5 (31%) | ||||
| Leukocytes, 109/L | 31 (3-217) | 32 (5-217) | 29 (3-167) | .736 | 35 (9-217) | 29 (3-167) | .064 | 34 (5-217) | 22 (3-140) | .045 | 31 (3-217) | 33 (6-691) | .813 |
| Platelets, 109/L | 67 (5-530) | 73 (12-530) | 56 (5-262) | .226 | 73 (5-530) | 53 (11-348) | .342 | 69 (5-530) | 56 (11-262) | .600 | 72 (5-530) | 30 (15-211) | .220 |
| Hemoglobin, g/dL | 9.3 (3.4-13.5) | 9.0 (3.4-13.5) | 9.5 (4.0-11.8) | .350 | 9.0 (4.1-11.9) | 9.5 (3.4-13.5) | .120 | 9.1 (3.4-13.5) | 9.9 (6.0-11.4) | .220 | 9.2 (3.4-13.5) | 9.4 (6.9-11.8) | .910 |
| Myeloblasts (PB), % | 2 (0-18) | 2 (0-16) | 2 (0-18) | .336 | 2 (0-16) | 2 (0-18) | .517 | 2 (0-13) | 2 (0-18) | .915 | 2 (0-18) | 1.5 (0-9) | .254 |
| Myeloblasts (BM), % | 6 (0-28) | 6 (0-28) | 6 (0-19) | .946 | 4 (0-17) | 6 (0-28) | .001 | 6 (0-20) | 6 (0-28) | .240 | 6 (0-28) | 5 (0-11) | .342 |
| Missing | 6 | ||||||||||||
| Monocytes (PB), % | 18 (0-55) | 18 (0-55) | 18 (5-45) | .786 | 16 (0-46) | 21 (2-55) | .065 | 17 (0-55) | 20 (4-45) | .350 | 19 (0-55) | 16 (5-42) | .362 |
| Monocytes (BM), % | 6 (0-34) | 6 (0-22) | 5 (0-34) | .919 | 5 (0-21) | 6 (0-34) | .203 | 6 (0-34) | 5 (0-26) | .532 | 6 (0-34) | 6 (1-18) | .890 |
| Missing | 6 | ||||||||||||
| Spleen size at diagnosis, cm below the costal margin | 5 (0-15) | 5 (0-15) | 5 (0-15) | .970 | 5 (0-15) | 5 (0-15) | .719 | 5 (0-15) | 5 (0-15) | .947 | 5 (0-15) | 5 (0-12) | .677 |
| Missing | 3 | ||||||||||||
| HbF (age-adjusted) | .008 | .004 | .172 | .176 | |||||||||
| Normal | 24 (25%) | 20 (35%) | 4 (10%) | 17 (71%) | 7 (29%) | 21 (28%) | 3 (14%) | 23 (27%) | 1 (8%) | ||||
| Elevated | 73 (75%) | 38 (65%) | 35 (90%) | 26 (36%) | 46 (64%) | 54 (72%) | 19 (86%) | 61 (73%) | 12 (92%) | ||||
| Missing | 30 | ||||||||||||
| Karyotype | > .999 | .010 | .023 | .226 | |||||||||
| Normal | 86 (71%) | 55 (71%) | 31 (71%) | 46 (82%) | 39 (60%) | 74 (75%) | 12 (50%) | 73 (68%) | 13 (87%) | ||||
| Aberrant | 36 (29%) | 23 (29%) | 13 (29%) | 10 (18%) | 26 (40%) | 24 (25%) | 12 (50%) | 34 (32%) | 2 (13%) | ||||
| Missing | 5 | ||||||||||||
| DNA source | .854 | > .999 | .138 | .598 | |||||||||
| PB | 57 | 37 (46%) | 20 (44%) | 26 (45%) | 31 (46%) | 48 (49%) | 9 (32%) | 51 (46%) | 6 (38%) | ||||
| BM | 70 | 44 (54%) | 26 (56%) | 32 (55%) | 37 (54%) | 51 (52%) | 19 (68%) | 60 (54%) | 10 (62%) | ||||
| Mutation | .076 | .320 | .778 | .411 | |||||||||
| NF1 | 16 (13%) | 9 (11%) | 7 (15%) | .417 | 5 (9%) | 11 (17%) | .192 | 12 (12%) | 4 (15%) | .529 | 14 (13%) | 2 (12%) | .449 |
| PTPN11 | 48 (38%) | 26 (32%) | 22 (49%) | .089 | 19 (33%) | 29 (43%) | .150 | 36 (37%) | 12 (44%) | .391 | 39 (35%) | 9 (56%) | .174 |
| KRAS/NRAS | 30 (23%) | 22 (27%) | 8 (18%) | .395 | 16 (28%) | 14 (21%) | .536 | 25 (25%) | 5 (19%) | .806 | 29 (26%) | 1 (6%) | .116 |
| CBL | 16 (13%) | 13 (16%) | 3 (7%) | .126 | 9 (15%) | 7 (10%) | .290 | 14 (14%) | 2 (7%) | .406 | 14 (13%) | 2 (13%) | .855 |
| No mutation | 16 (13%) | 11 (14%) | 5 (11%) | 9 (15%) | 6 (9%) | 12 (12%) | 4 (15%) | 14 (13%) | 2 (13%) | ||||
| Missing | 1 | ||||||||||||
| Survival | .001 | .240 | .505 | .006 | |||||||||
| Alive | 81(64%) | 61 (75%) | 20 (44%) | 40 (69%) | 40(59%) | 65 (66%) | 16 (57%) | 76 (69%) | 5 (31%) | ||||
| Dead | 46 (36%) | 20 (25%) | 26 (56%) | 18 (31%) | 28 (41%) | 34 (34%) | 12 (43%) | 35 (31%) | 11 (69%) | ||||
| Alive after HSCT | .079 | .832 | .799 | .094 | |||||||||
| Yes | 63 (66%) | 45 (71%) | 18 (53%) | 30 (67%) | 33 (64%) | 50 (66%) | 13 (62%) | 59 (68%) | 4 (40%) | ||||
| No | 34 (34) | 18 (29%) | 16 (47%) | 15 (33%) | 19 (36%) | 26 (34%) | 8 (38%) | 28 (32%) | 6 (60%) | ||||
| No HSCT | |||||||||||||
| Relapse after HSCT | < .001 | .070 | .265 | .021 | |||||||||
| Yes | 26 (27%) | 9 (14%) | 17 (50%) | 37 (82%) | 34 (65%) | 18 (24%) | 8 (38%) | 20 (23%) | 6 (60%) | ||||
| No | 71 (73%) | 54 (86%) | 17 (50%) | 8 (18%) | 18 (35%) | 58 (76%) | 13 (62%) | 67 (77%) | 4 (40%) |
| . | Total cohort . | Normal BMP4 methylation . | BMP4 hyper-methylation . | P . | Normal CALCA methylation . | CALCA hyper-methylation . | P . | Normal CDKN2B methylation . | CDKN2B hyper-methylation . | P . | Normal RARB methylation . | RARB hyper-methylation . | P . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 127 | 81 | 46 | 58 | 68 | 99 | 28 | 111 | 16 | ||||
| Median age, years (range) | 1.4 (0.1-12.2) | 1.1 (0.1-7.0) | 3.6 (0.2-12.2) | < .001 | 0.7 (0.1-3.6) | 2.9 (0.2-12.2) | < .001 | 1.2 (0.1-6.6) | 4.0 (0.3-12.2) | < .001 | 1.4 (0.1-12.2) | 3.7 (0.8-6.6) | < .001 |
| Sex | .701 | .710 | > .999 | .787 | |||||||||
| Male | 82 (65%) | 51 (63%) | 31 (67%) | 36 (62%) | 45 (66%) | 64 (65%) | 18 (64%) | 71 (64%) | 11 (69%) | ||||
| Female | 45 (35%) | 30 (37%) | 15 (33%) | 22(38%) | 23 (34%) | 35 (35%) | 10 (36%) | 40 (36%) | 5 (31%) | ||||
| Leukocytes, 109/L | 31 (3-217) | 32 (5-217) | 29 (3-167) | .736 | 35 (9-217) | 29 (3-167) | .064 | 34 (5-217) | 22 (3-140) | .045 | 31 (3-217) | 33 (6-691) | .813 |
| Platelets, 109/L | 67 (5-530) | 73 (12-530) | 56 (5-262) | .226 | 73 (5-530) | 53 (11-348) | .342 | 69 (5-530) | 56 (11-262) | .600 | 72 (5-530) | 30 (15-211) | .220 |
| Hemoglobin, g/dL | 9.3 (3.4-13.5) | 9.0 (3.4-13.5) | 9.5 (4.0-11.8) | .350 | 9.0 (4.1-11.9) | 9.5 (3.4-13.5) | .120 | 9.1 (3.4-13.5) | 9.9 (6.0-11.4) | .220 | 9.2 (3.4-13.5) | 9.4 (6.9-11.8) | .910 |
| Myeloblasts (PB), % | 2 (0-18) | 2 (0-16) | 2 (0-18) | .336 | 2 (0-16) | 2 (0-18) | .517 | 2 (0-13) | 2 (0-18) | .915 | 2 (0-18) | 1.5 (0-9) | .254 |
| Myeloblasts (BM), % | 6 (0-28) | 6 (0-28) | 6 (0-19) | .946 | 4 (0-17) | 6 (0-28) | .001 | 6 (0-20) | 6 (0-28) | .240 | 6 (0-28) | 5 (0-11) | .342 |
| Missing | 6 | ||||||||||||
| Monocytes (PB), % | 18 (0-55) | 18 (0-55) | 18 (5-45) | .786 | 16 (0-46) | 21 (2-55) | .065 | 17 (0-55) | 20 (4-45) | .350 | 19 (0-55) | 16 (5-42) | .362 |
| Monocytes (BM), % | 6 (0-34) | 6 (0-22) | 5 (0-34) | .919 | 5 (0-21) | 6 (0-34) | .203 | 6 (0-34) | 5 (0-26) | .532 | 6 (0-34) | 6 (1-18) | .890 |
| Missing | 6 | ||||||||||||
| Spleen size at diagnosis, cm below the costal margin | 5 (0-15) | 5 (0-15) | 5 (0-15) | .970 | 5 (0-15) | 5 (0-15) | .719 | 5 (0-15) | 5 (0-15) | .947 | 5 (0-15) | 5 (0-12) | .677 |
| Missing | 3 | ||||||||||||
| HbF (age-adjusted) | .008 | .004 | .172 | .176 | |||||||||
| Normal | 24 (25%) | 20 (35%) | 4 (10%) | 17 (71%) | 7 (29%) | 21 (28%) | 3 (14%) | 23 (27%) | 1 (8%) | ||||
| Elevated | 73 (75%) | 38 (65%) | 35 (90%) | 26 (36%) | 46 (64%) | 54 (72%) | 19 (86%) | 61 (73%) | 12 (92%) | ||||
| Missing | 30 | ||||||||||||
| Karyotype | > .999 | .010 | .023 | .226 | |||||||||
| Normal | 86 (71%) | 55 (71%) | 31 (71%) | 46 (82%) | 39 (60%) | 74 (75%) | 12 (50%) | 73 (68%) | 13 (87%) | ||||
| Aberrant | 36 (29%) | 23 (29%) | 13 (29%) | 10 (18%) | 26 (40%) | 24 (25%) | 12 (50%) | 34 (32%) | 2 (13%) | ||||
| Missing | 5 | ||||||||||||
| DNA source | .854 | > .999 | .138 | .598 | |||||||||
| PB | 57 | 37 (46%) | 20 (44%) | 26 (45%) | 31 (46%) | 48 (49%) | 9 (32%) | 51 (46%) | 6 (38%) | ||||
| BM | 70 | 44 (54%) | 26 (56%) | 32 (55%) | 37 (54%) | 51 (52%) | 19 (68%) | 60 (54%) | 10 (62%) | ||||
| Mutation | .076 | .320 | .778 | .411 | |||||||||
| NF1 | 16 (13%) | 9 (11%) | 7 (15%) | .417 | 5 (9%) | 11 (17%) | .192 | 12 (12%) | 4 (15%) | .529 | 14 (13%) | 2 (12%) | .449 |
| PTPN11 | 48 (38%) | 26 (32%) | 22 (49%) | .089 | 19 (33%) | 29 (43%) | .150 | 36 (37%) | 12 (44%) | .391 | 39 (35%) | 9 (56%) | .174 |
| KRAS/NRAS | 30 (23%) | 22 (27%) | 8 (18%) | .395 | 16 (28%) | 14 (21%) | .536 | 25 (25%) | 5 (19%) | .806 | 29 (26%) | 1 (6%) | .116 |
| CBL | 16 (13%) | 13 (16%) | 3 (7%) | .126 | 9 (15%) | 7 (10%) | .290 | 14 (14%) | 2 (7%) | .406 | 14 (13%) | 2 (13%) | .855 |
| No mutation | 16 (13%) | 11 (14%) | 5 (11%) | 9 (15%) | 6 (9%) | 12 (12%) | 4 (15%) | 14 (13%) | 2 (13%) | ||||
| Missing | 1 | ||||||||||||
| Survival | .001 | .240 | .505 | .006 | |||||||||
| Alive | 81(64%) | 61 (75%) | 20 (44%) | 40 (69%) | 40(59%) | 65 (66%) | 16 (57%) | 76 (69%) | 5 (31%) | ||||
| Dead | 46 (36%) | 20 (25%) | 26 (56%) | 18 (31%) | 28 (41%) | 34 (34%) | 12 (43%) | 35 (31%) | 11 (69%) | ||||
| Alive after HSCT | .079 | .832 | .799 | .094 | |||||||||
| Yes | 63 (66%) | 45 (71%) | 18 (53%) | 30 (67%) | 33 (64%) | 50 (66%) | 13 (62%) | 59 (68%) | 4 (40%) | ||||
| No | 34 (34) | 18 (29%) | 16 (47%) | 15 (33%) | 19 (36%) | 26 (34%) | 8 (38%) | 28 (32%) | 6 (60%) | ||||
| No HSCT | |||||||||||||
| Relapse after HSCT | < .001 | .070 | .265 | .021 | |||||||||
| Yes | 26 (27%) | 9 (14%) | 17 (50%) | 37 (82%) | 34 (65%) | 18 (24%) | 8 (38%) | 20 (23%) | 6 (60%) | ||||
| No | 71 (73%) | 54 (86%) | 17 (50%) | 8 (18%) | 18 (35%) | 58 (76%) | 13 (62%) | 67 (77%) | 4 (40%) |
Hypermethylation was defined as a level of methylation exceeding 3 standard deviations from the mean observed in 15 healthy control individuals. For categorical variables, column percentages add to 100%. For continuous variables, median values and range are given. P values for significance of associations are based on the χ2 test for categorical variables and on the Wilcoxon Mann-Whitney test for continuous variables.