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