DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets
Abstract
Simple Summary
Abstract
1. Introduction
2. Results
2.1. Linking Expression of DNA Repair Genes and AML Patient Overall Survival
2.2. GEP-Based DNA Repair Score for Predicting CN-AML Patients’ Survival
2.3. DNA Repair Score and NPM1 / FLT3 Mutational Status Combination as Prognosis Factors in CN-AML
3. Discussion
4. Materials and Methods
4.1. Patients and Gene Expression Data
4.2. Selection of Prognostic Genes
4.3. Building DNA Repair Gene Expression-Based Risk Score
4.4. Validation of the DNA Repair Score on Validation Cohort
4.5. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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DNA Repair Pathway | Probe Set | Gene Symbol | Benjamini–Hochberg Corrected p-Value | Hazard Ratio | Prognosis |
---|---|---|---|---|---|
Base Excision Repair pathway (BER) | 210027_s_at 209731_at 202330_s_at 203655_at | APEX1 NTHL1 UNG XRCC1 | 0.02 0.0016 0.0095 0.022 | 1.6 1.9 2 1.6 | Bad Bad Bad Bad |
Fanconi pathway (FANC) | 209902_at 214727_at 203719_at 203678_at 221206_at 219317_at | ATR BRCA2 ERCC1 FAN1 PMS2 /// PMS2CL POLI | 0.0048 0.0049 0.0037 0.0028 0.024 0.0016 | 1.8 0.58 1.9 1.8 1.8 1.9 | Bad Good Bad Bad Bad Bad |
Homologous Recombination Repair pathway (HRR) | 214727_at 205395_s_at 205647_at 206092_x_at 212275_s_at 207598_x_at | BRCA2 MRE11A RAD52 RTEL1 SRCAP XRCC2 | 0.0049 0.015 0.044 0.00047 0.014 0.007 | 0.58 1.8 1.9 2.5 0.6 1.7 | Good Bad Bad Bad Good Bad |
Mismatch Repair pathway (MMR) | 205887_x_at 221206_at 1053_at | MSH3 PMS2 /// PMS2CL RFC2 | 0.000043 0.024 0.023 | 2.8 1.8 1.6 | Bad Bad Bad |
Nucleotide Excision Repair pathway (NER) | 201405_s_at 213579_s_at 203719_at 205162_at 223758_s_at 201046_s_at 205672_at 203655_at | COPS6 EP300 ERCC1 ERCC8 GTF2H2 RAD23A XPA XRCC1 | 0.011 0.019 0.0037 0.04 0.033 0.0067 0.0035 0.022 | 1.7 0.59 1.9 1.5 1.5 0.53 1.8 1.6 | Bad Good Bad Bad Bad Good Bad Bad |
DNA Repair Pathway Score | Univariate Cox Analysis | Multivariate Cox Analysis | ||
---|---|---|---|---|
HR | p-Value | HR | p-Value | |
BER score | 1.97 | 1.44 × 10−3 | 0.93 | NS |
FANC score | 2.32 | 2.98 × 10−5 | 1.30 | NS |
HRR score | 3.23 | 2.16 × 10−7 | 2.36 | 5.89 × 10−4 |
MMR score | 2.80 | 1.59 × 10−4 | 1.58 | NS |
NER score | 3.83 | 2.90 × 10−4 | 2.54 | 1.66 × 10−2 |
Scores | Univariate Cox Analysis | Multivariate Cox Analysis | ||
---|---|---|---|---|
HR | p-Value | HR | p-Value | |
DNA repair score | 2.76 | 1.49 × 10−8 | 2.66 | 5.1 × 10−8 |
NPM1 mutation/FLT3-ITD classification | 1.81 | 1.18 × 10−4 | 1.76 | 6.2 × 10−4 |
Classification According to DNA Repair Score | ||||
---|---|---|---|---|
Group I 0 point | Group II 1 point | Group III 2 points | ||
NPM1 and FLT3 mutational status | NPM1+ and FLT3-ITD- 0 point | 0 | 1 | 2 |
NPM1+ and FLT3-ITD+ or NPM1- and FLT3-ITD- 1 point | 1 | 2 | 3 | |
NPM1- and FLT3-ITD+ 2 points | 2 | 3 | 4 |
Target | Drug | Cancer | Phase | Intervention | Identifier |
---|---|---|---|---|---|
Base Excision Repair (BER) Pathway | |||||
APEX1 | TRC-102 | Solid tumors & lymphomas | I/II | TRC-102 + temozolomide | NCT01851369 |
PARP1/2 | Niraparib | Pancreatic ADK | II | Niraparib alone | NCT03601923 |
Olaparib | Lymphomas (B/T/Hodgkin) | I | Olaparib + high-dose chemotherapy + ASCT | NCT03259503 | |
Olaparib | AML or MDS with IDH1/2 mutation | II | Olaparib alone | NCT03953898 | |
Talazoparib | R/R AML CD33+ | I/II | Talazoparib + GO | NCT04207190 | |
Talazoparib | AML | I/II | Talazoparib + Decitabine | NCT02878785 | |
Veliparib | Myeloproliferative disorders | II | Carboplatin + Topotecan +/− Veliparib | NCT03289910 | |
Homologous Recombination Repair (HRR) Pathway | |||||
ATM | AZD1390 | Glioblastoma | I | AZD1390 + radiotherapy | NCT03423628 |
CHEK-1/2 | Prexasertib | R/R medulloblastoma | I | Prexasertib + Gemcitabine or Cyclophosphamide | NCT04023669 |
RAD51 | CYT-0851 | Solid tumors & B-cell lymphomas | I/II | CYT-0851 alone | NCT03997968 |
Fanconi (FANC) Pathway | |||||
ATM | (see above) | ||||
ATR | Ceralasertib | R/R non-Hodgkin’s lymphoma | I | Ceralasertib + Acalabrutinib | NCT03527147 |
M6620 | Solid tumors | II | MS6620 alone | NCT03718091 | |
RAD51 | (see above) | ||||
Nucleotide Excision Repair (NER) pathway | |||||
CDK7 | LY3405105 | Solid tumors | I | LY3405105 alone | NCT03770494 |
SY5609 | Solid tumors | I | SY5609 +/− Fulvestrant | NCT04247126 | |
CT7001 | Solid tumors | I/II | CT7001 +/− Fulvestrant | NCT03363893 | |
Others | |||||
WEE1 | Adavosertib | SQCLC | II | Adavosertib + Paclitaxel + Carboplatin | NCT02513563 |
PARP1/2 + ATR or WEE1 | Olaparib Ceralasertib Adavosertib | Metastatic triple negative breast cancer | II | Olaparib alone or Olaparib + Ceralasertib or Olaparib + Adavosertib | NCT03330847 |
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Gabellier, L.; Bret, C.; Bossis, G.; Cartron, G.; Moreaux, J. DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets. Cancers 2020, 12, 2874. https://doi.org/10.3390/cancers12102874
Gabellier L, Bret C, Bossis G, Cartron G, Moreaux J. DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets. Cancers. 2020; 12(10):2874. https://doi.org/10.3390/cancers12102874
Chicago/Turabian StyleGabellier, Ludovic, Caroline Bret, Guillaume Bossis, Guillaume Cartron, and Jérôme Moreaux. 2020. "DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets" Cancers 12, no. 10: 2874. https://doi.org/10.3390/cancers12102874
APA StyleGabellier, L., Bret, C., Bossis, G., Cartron, G., & Moreaux, J. (2020). DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets. Cancers, 12(10), 2874. https://doi.org/10.3390/cancers12102874