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RAS pathway alterations in pediatric AML
Table 1. Summary of characteristics of pediatric acute myeloid leukemia patients with NF1 alteration.
UPN Nucleotide Amino acid VAF change* change*
50 c.G4681T p.E1561X 0.94
262 c.2027dupC p.I679Dfs21X 0.28 c.6862_6863insCG p.P2289Rfs10X 0.26
367 c.966_967insGA p.A323Efs54X 0.28 c.2027dupC p.I679Dfs21X 0.08
57 c.C3721T R1241X 0.83 105 - - -
Copy Start Sex Age, WBC, Cytogenetics Additional CR Relapse Event SCT Prognosis
number to end
- - - -
--
1.16 1225849-29422297 0.99 29485961-30325657
1.02 27009658-29588669 0.29 29626467-29679186 0.95 29683418-30325657
y ×109/L genetic aberrations
M 13.7 19.9 45,XY,-7[13]/46,XY[7] KIT - - + + Death M 12.3 159.3 46,XY,inv(16) CBL, + - - - Alive
(p13q22)[20] NRAS
M 7 9.9 47,XY,+11[18]/54, PTPN11 + - - - Alive idem,+X,+10,+11,+13,+14,
+20,+21[1]/46,XY[1]
M 15.2 69.0 #1 RUNX1, - - + + Death
BCORL1 M 10.8 15.5 #2 ASXL1
+ + + + Death + + + + Death
+ - - - Alive
415 -
- -
1.26 1225849-29422297 F 12.3 1.9 45,XX,ins(1;?) PTPN11
333 ---
1.04 29485961-30325657
0.22 29485961-29588669
0.94 29626467-30325657
F 9.8
(q21;?), add(4)(q12), add(7)(q36), der(17;18) (q10;q10)[20]
4.1 46,XX,t(8;12) BCORL1 (q11.2;p11.2)[20]
UPN:unique patient number;VAF:variant allele frequency;WBC:white blood cell count;CR:complete remission;SCT:stem cell transplantation;M:male,F:female;y:years;SCT:stem cell trans- plantation.*NCBI reference sequence;NM_00267.#1 47,X,-Y,add(3)(q11.2),+6,add(6)(p21)x2,+7,del(8)(q24)der(8)t(1;8)(q11;q24),del(11)(q?),add(17)(p11.2)[7]/48,sl,+22[6]/47,sl,-14,+mar1[2] #2 46,XY,+Y,add(1)(p11),del(2)(q?),del(5)(q?),add(8)(p11.2),-9,-9,-11,-17,add(18)(q21),-19,add(22)(q11.2),+del(?)t(?;11)(?;q13),+mar1,+mar2,+mar3[2]/88,sl,×2,-3,-del(5)×2,-6,+9,-20,-20,-21, -mar1,-mar3×2,+5mar[1]/47,XY,+Y[9]
Supplementary Figure S4). With respect to prognosis, patients with CBL mutations were divided into two dis- tinct groups based on the presence of CBF. All CBF-AML patients with CBL mutations achieved complete remis- sion and were alive. However, all non-CBF-AML patients relapsed and died (Table 2).
Next, we performed multivariate analysis using the Cox regression analysis to determine the prognostic impacts of RAS pathway alterations (Table 3). Besides RAS pathway mutations, we used t(8;21)(q22;q22)/RUNX1-RUNX1T1, CBFB-MYH11, monosomy 7, complex karyotype, FLT3- ITD, 5q-, FUS-ERG, NUP98-NSD1, and PRDM16 high expression as explanatory variables in the multivariate analysis; these cytogenetic aberrations were used for risk classification in the AML-05 trials (Online Supplementary Figure S1) or were recently shown to affect the progno- sis.33,44 Remarkably, NF1 alterations were associated with inferior OS in multivariate analysis (hazard ratio [HR] 4.109; 95% CI:, 1.471–11.48; P=0.007] (Table 3). In uni- variate analysis, PTPN11 mutation was associated with inferior EFS (HR 2.142; 95% CI: 1.157-3.965; P=0.015) (Table 3). However, PTPN11 mutation was not associated with inferior EFS (HR 1.239; 95% CI: 0.616–2.494; P=0.548) in multivariate analysis; this indicated that co- occurring aberrations contributed to worse outcomes (Table 3). In multivariate analysis, NRAS mutation was a favorable prognostic factor for both OS and EFS (OS: HR 0.309; 95% CI: 0.112–0.849; P=0.023; EFS: HR, 0.530; 95% CI: 0.293–0.961; P=0.037) (Table 3). These results suggested that alterations of NF1 and NRAS were inde- pendent predictors of prognosis in pediatric patients with AML. CBFB-MYH11 could not be evaluated accurately for OS in the Cox regression analysis because 27 patients with CBFB-MYH11 enrolled in this study were all alive. The OS of patients with CBFB-MYH11 was significantly better than that of patients without CBFB-MYH11 in the Kaplan–Meier method (P=0.005). (Online Supplementary Figure S5)
Discussion
In this study, we detected RAS pathway alterations in 80 (24.4%) of the 328 patients with AML (NF1 [n=7, 2.1%], PTPN11 [n=15, 4.6%], CBL (n=6, 1.8%], NRAS [n=44, 13.4%], KRAS [n=12, 3.7%]). Most of these were mutually exclusive and were also mutually exclusive with aberrations involving other signal transduction pathways such as FLT3-ITD and KIT mutation (Figure 1).
Loss of the wild-type allele of NF1, either through dele- tions or mutations, has been implicated in the pathogenesis of hematological malignancies.11 We have summarized pre- vious reports on NF1 alterations in adult and pediatric AML in the Online Supplementary Table S5. NF1 deletions have been reported in 3.5–10.5% of adult patients with AML; in addition, 20-50% of patients with NF1 deletions had con- comitant NF1 mutations in the remaining allele.14-16 In this study, the frequency of NF1 alterations was less than that in previous reports pertaining to adult patients. In addition, at least four of the seven (57%) patients with NF1 alterations had bi-allelic NF1 inactivation (Table 1). NF1 alterations have been frequently reported in complex karyotype AML; in addition, NF1 alterations were shown to be associated with poor prognosis in adult AML.3 In the contemporary lit- erature, there are few reports about NF1 alteration in pedi- atric AML. Balgobind et al. detected NF1 deletion in two of the 71 AML patients with KMT2A rearrangement, one of whom experienced relapse.11 Consistent with previous reports, NF1 alterations were frequently detected in com- plex karyotype, and were associated with poor OS in this study (Figure 3; Table 3). None of the four patients with relapse or induction failure were rescued by SCT (Figure 1; Table 1). Our findings suggest that more intensive primary chemotherapy may be an option to rescue AML patients with NF1 alterations including use of novel molecular tar- geted therapy such as mTOR inhibitors. In a study by Parkin et al., NF1 null blasts showed sensitivity to rapamycin-induced apoptosis.3,14
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