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Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?

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Abstract

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.

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Funding

This study was partially supported by the National Council of Technological and Scientific Development (CNPq) (Grant Nos. #420501/2018-5 and #424542/2016-1).

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Author notes

  1. Howard Lopes Ribeiro Junior and Roberta Taiane Germano de Oliveira have equal credits.

Authors and Affiliations

  1. Cancer Cytogenomic Laboratory, Center for Research and Drug Development (NPDM), Federal University of Ceara, 1000 Coronel, Nunes de Melo St. Rodolfo Teófilo, Fortaleza, Ceara, 60430-275, Brazil

    Howard Lopes Ribeiro Junior, Roberta Taiane Germano de Oliveira, Daniela de Paula Borges, Marília Braga Costa, Izabelle Rocha Farias, Antônio Wesley Araújo dos Santos, Silvia Maria Meira Magalhães & Ronald Feitosa Pinheiro

  2. Post-Graduate Program in Medical Science, Federal University of Ceara, Fortaleza, Ceara, Brazil

    Howard Lopes Ribeiro Junior, Roberta Taiane Germano de Oliveira, Daniela de Paula Borges, Marília Braga Costa, Izabelle Rocha Farias, Antônio Wesley Araújo dos Santos, Silvia Maria Meira Magalhães & Ronald Feitosa Pinheiro

  3. Post-Graduate Program of Pathology, Federal University of Ceara, Fortaleza, Ceara, Brazil

    Ronald Feitosa Pinheiro

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  1. Howard Lopes Ribeiro Junior
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Contributions

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.

Corresponding author

Correspondence to Ronald Feitosa Pinheiro.

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The authors declare that they have no competing interest.

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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.

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Informed consent was obtained from all individual participants included in the study.

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Junior, H.L.R., de Oliveira, R.T.G., de Paula Borges, D. et al. Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?. Med Oncol 36, 99 (2019). https://doi.org/10.1007/s12032-019-1324-7

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  • DOI: https://doi.org/10.1007/s12032-019-1324-7

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