Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?
Cancer-specific defects in DNA repair pathways create the opportunity to employ synthetic lethality approach. Recently, GEMA (gene expression and mutation analysis) approach detected insufficient expression of BRCA or NHEJ (non-homologous end joining) to predict PARP inhibitors response. We evaluated a possible role of DNA repair pathways using gene expression of single-strand break (XPA, XPC, XPG/ERCC5, CSA/ERCC8, and CSB/ERCC6) and double-strand break (ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6, LIG4) in 92 patients with myelodysplastic syndrome (73 de novo, 9 therapy-related (t-MDS). Therapy-related MDS (t-MDS) demonstrated a significant downregulation of axis BRCA1-BRCA2-RAD51 comparing to normal controls (p = 0.048, p = 0.001, p = 0.001). XRCC6 showed significantly low expression in de novo MDS comparing to controls (p = 0.039) and for patients who presented chromosomal abnormalities (p = 0.047). Downregulation of LIG4 was consistently associated with poor prognostic markers in de novo MDS (hemoglobin < 8 g/dL (p = 0.040), neutrophils < 800/mm3 (p < 0.001), patients with excess of blasts (p = 0.001), very high (p = 0.002)/high IPSS-R (p = 0.043) and AML transformation (p < 0.001). We also performed an evaluation of GEPIA Database in 30 cancer types and detected a typical pattern of downregulation as here presented in primary or secondary MDS. All these results suggest synthetic lethality approach can be tested with DNA repair genes (beyond that of BRCA1/2 status) for de novo and therapy-related myelodysplastic syndrome and may encourage clinical trials evaluating the use of PARP1 inhibitors in MDS.
KeywordsMyelodysplastic syndrome Synthetic lethality DNA repair Gene expression
HLRJ, RTGO, SMMM and RFP designed the study, provided patient materials and were responsible for collection and assembly of data. HLRJ, RTGO, AWAS, MBC, IRF and DPB performed the molecular procedures and analyzed the data. All drafted and edited the manuscript. All authors have approved the final version of manuscript before publication.
This study was partially supported by the National Council of Technological and Scientific Development (CNPq) (Grant Nos. #420501/2018-5 and #424542/2016-1).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interest.
All procedures were approved by the Ethics Committee of UFC (#1.292.509) and are in accordance with the 1964 Helsinki declaration and its later amendments.
Informed consent was obtained from all individual participants included in the study.
- 1.Schanz J, Cevik N, Fonatsch C, et al. Detailed analysis of clonal evolution and cytogenetic evolution patterns in patients with myelodysplastic syndromes (MDS) and related myeloid disorders. Blood Cancer J. 2018;8(3):28. https://doi.org/10.1038/s41408-018-0061-z.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Scharer OS. Nucleotide excision repair in eukaryotes. Department of Pharmacological Sciences and Department of Chemistry, Stony Brook University, Stony Brook, New York 11974-3400. Cold Spring Harb Perspect Biol. 2013;5:a012609. https://doi.org/10.1101/cshperspect.a012609.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Petruseva IO, Evdokimov AN, Lavrik OI. Molecular mechanism of global genome nucleotide excision repair. Acta Nat. 2014;6(1):20.Google Scholar
- 19.Economopoulou P, Pappa V, Kontsioti F, et al. Expression analysis of proteins involved in the non homologous end joining DNA repair mechanism in the bone marrow of adult de novo myelodysplastic syndromes. Ann Hematol. 2010;89(3):233–9. https://doi.org/10.1007/s00277-009-0823-6.CrossRefPubMedGoogle Scholar
- 22.McGowan-Jordan J, Simons A, Schmid M. ISCN 2016: an international system for human cytogenomic nomenclature (2016). Cytogenet Genom Res. 2016;149:1–2.Google Scholar
- 25.Tang Z, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017. https://doi.org/10.1093/nar/gkx247.10.1093/nar/gkx247.CrossRefPubMedPubMedCentralGoogle Scholar