Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications
Abstract
:1. Introduction
2. Results
2.1. Patient Characteristics and Their Redistribution in New Diagnostic Categories
2.2. Molecular Characterization
2.2.1. Somatic Variants
2.2.2. Somatic Oncogenic or Likely Oncogenic (O/LO) Mutations
2.2.3. RUNX1 Mutations
2.2.4. Pattern of Co-Occurrence and Mutual Exclusivity
2.2.5. Copy-Number Analysis
2.3. Characteristics of AML-DD/NOS Defined by New Classifications
2.4. Impact of Mutational Burden on Outcome
3. Discussion
4. Materials and Methods
4.1. Patient Selection
4.2. Sequencing Procedures
4.3. Filtering Criteria
4.4. Copy Number Analysis
4.5. Other Tools Used for Genetic Lesion Detection
4.6. Statistical Analysis and Plotting
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Total (n = 69) | AML-MRC (n = 27) | AML-NOS (n = 26) | RUNX1m AML (n = 16) | p | |
---|---|---|---|---|---|
Median age, years (range) | 58 (24–81) | 61 (24–78) | 56 (25–77) | 58 (24–81) | 0.69 |
Female sex, n (%) | 30 (43) | 10 (37) | 14 (54) | 6 (37) | 0.41 |
WBC (×109/L), median (range) | 5.9 (0.5–171) | 6.6 (1–171) | 5 (0.5–143) | 5.7 (0.7–132) | 0.93 |
BM blast count, median (range) | 57 (10–98) | 39 (10–96) | 64 (17–98) | 78 (22–91) | 0.002 |
PB blast count, median (range) | 23 (0–100) | 15 (0–92) | 30 (0–100) | 61 (0–95) | 0.04 |
Normal karyotype, n (%) | 43 (67) | 16 (59) | 15 (62) | 12 (92) | 0.09 |
ELN22 defined adverse risk, n (%) | 51 (74) | 23 (85) | 12 (46) | 16 (100) | NA |
AML-MRC criteria | |||||
Previous MDS, n (%) | 11 (16) | 11 (39) | 0 | 0 | NA |
Morphologic dysplasia, n (%) | 23 (33) | 23 (82) | 0 | 0 | NA |
MDS-defining cytogenetics, n (%) | 4 (6) | 4 (15) | 0 | 0 | NA |
Treatment received | |||||
Intensive induction chemotherapy, n (%) | 59 (85) | 22 (81) | 22 (85) | 15 (94) | 0.62 |
Allogeneic HCT, n (%) | 42 (61) | 15 (55) | 15 (62) | 12 (92) | 0.42 |
Autologous HCT, n (%) | 5 (7) | 1 (4) | 3 (11) | 1 (6) | 0.73 |
Disease response after induction (n = 58) | |||||
Complete response, n (%) | 52 (90) | 18 (82) | 19 (86) | 14 (93) | 0.87 |
Refractory disease, n (%) | 6 (10) | 3 (13) | 2 (9) | 1 (7) | 0.87 |
Early death, n (%) | 2 (3) | 1 (4) | 1 (5) | 0 | 1 |
Total (n = 26) | AML-MRC (n = 10) | RUNX1m AML (n = 16) | p | |
---|---|---|---|---|
Median age, years (range) | 58 (24–81) | 65 (41–78) | 58 (24–81) | 0.19 |
Female sex, n (%) | 9 (35) | 3 (30) | 6 (37) | 1 |
WBC (×109/L), median (range) | 7.8 (0.7–134) | 12.7 (1.7–134) | 5.7 (0.7–132) | 0.34 |
BM blast count, median (range) | 67 (21–91) | 49 (21–81) | 78 (22–91) | 0.02 |
PB blast count, median (range) | 27 (0–95) | 16 (0–72) | 61 (0–95) | 0.04 |
Cytogenetics (n = 65) | ||||
Normal karyotype, n (%) | 18 (69) | 6 (60) | 12 (92) | 0.13 |
Number of variants *, median (range) | 6 (1–12) | 5.5 (3–10) | 6 (1–12) | 0.59 |
Number of mutations **, median (range) | 5 (1–7) | 4.5 (3–7) | 5 (1–7) | 0.5 |
Myelodysplasia-related and RUNX1 mutations **, median (range) | 1 (0–3) | 1 (0–3) | 1 (0–2) | 0.3 |
RUNX1 mutations (n = 31) | ||||
Missense variant | 9 | 4 | 5 | 1 |
Frameshift/Nonsense variant | 22 | 9 | 13 | 1 |
Multi-hit | 5 | 3 | 2 | NA |
Chr21q23 CN-LOH | 3 | 0 | 3 | NA |
Variant allele frequency (mean, range) | 0.4 (0.11–0.9) | 0.32 (0.11–0.55) | 0.47 (0.18–0.9) | 0.1 |
Sample ID | Chromosome | Start (GRCh38) | End (GRCh38) | Gene | HGSVc | HGSVp | VAF (%) |
---|---|---|---|---|---|---|---|
AQ5342 | chr2 (p25.3–p11.2) | 41,404 | 85,325,063 | DNMT3A | c.1742G>A | p.Trp581Ter | 71 |
AQ5327 | chr2 (p25.3–p23.3) | 41,404 | 27,616,502 | DNMT3A * | c.1813del | p.Leu605SerfsTer46 | 97 |
AQ5366 | chr6 (q27) | 166,931,095 | 170,583,760 | NA | |||
AQ5357 | chr7 (q11.21–q36.3) | 63,096,280 | 159,232,490 | EZH2 | c.203_204del | p.Val68AlafsTer13 | 85 |
AQ5390 | chr7 (q11.22–q36.3) | 70,768,153 | 159,232,490 | CUX1 | c.634C>T | p.Gln212Ter | 98 |
AQ5368 | chr11 (p15.5–p11.2) | 43,754,184 | 43,554,371 | NA | |||
AQ5359 | chr11 (p15.5–p11.2) | 199,813 | 45,812,493 | WT1 | c.1152dup | p.Arg385ThrfsTer5 | 79 |
AQ5344 | chr11 (p15.5–p13) | 199,813 | 35,968,505 | WT1 ** | c.1264+1G>C | 73 | |
AQ5340 | chr11 (q13.2–q25) | 66,551,501 | 134,857,757 | KMT2A-PTD | NA | ||
AQ5380 | chr3 (p26.3–p12.2) | 319,825 | 81,648,979 | NA | |||
AQ5383 | chr11 (q12.1–q25) | 57,688,772 | 134,857,757 | CBL | c.1228-1G>A | 88 | |
AQ5389 | chr11 (q13.1–q25) | 65,999,744 | 134,857,757 | KMT2A-PTD | NA | ||
AQ5351 | chr17 (q11.1–q25.3) | 27,280,695 | 83,054,873 | NF1 | c.4577+2T>G | 86 | |
AQ5395 | chr17 (p13.3–p11.2) | 161,952 | 21,016,024 | NA | |||
AQ5335 | chr21 (q11.2–q22.3) | 13,384,722 | 46,608,083 | RUNX1 | c.592G>T | p.Asp198Tyr | 29 |
AQ5363 | chr21(q11.2–q22.3) | 13,384,722 | 46,608,083 | NA | |||
AQ5331 | chr21 (q21.3–q22.3) | 29,591,425 | 46,608,083 | *** | |||
AQ5333 | chr21 (q22.11–q22.3) | 32,268,841 | 46,608,083 | RUNX1 | c.496C>T | p.Arg166Ter | 89 |
AQ5336 | chr21 (q22.11–q22.3) | 32,319,444 | 46,618,727 | RUNX1 | c.637C>T | p.Gln213Ter | 78 |
AQ5351 | chr22 (q11.1–q13.33) | 16,136,750 | 50,740,572 | NA |
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Guijarro, F.; Castaño-Díez, S.; Jiménez-Vicente, C.; Garrote, M.; Álamo, J.R.; Gómez-Hernando, M.; López-Oreja, I.; Morata, J.; López-Guerra, M.; López, C.; et al. Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications. Int. J. Mol. Sci. 2024, 25, 8669. https://doi.org/10.3390/ijms25168669
Guijarro F, Castaño-Díez S, Jiménez-Vicente C, Garrote M, Álamo JR, Gómez-Hernando M, López-Oreja I, Morata J, López-Guerra M, López C, et al. Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications. International Journal of Molecular Sciences. 2024; 25(16):8669. https://doi.org/10.3390/ijms25168669
Chicago/Turabian StyleGuijarro, Francesca, Sandra Castaño-Díez, Carlos Jiménez-Vicente, Marta Garrote, José Ramón Álamo, Marta Gómez-Hernando, Irene López-Oreja, Jordi Morata, Mònica López-Guerra, Cristina López, and et al. 2024. "Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications" International Journal of Molecular Sciences 25, no. 16: 8669. https://doi.org/10.3390/ijms25168669