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

Journal Article · Sun Dec 15 00:00:00 EST 2019 · Medical Oncology (Online)

DOI:https://doi.org/10.1007/S12032-019-1324-7· OSTI ID:22938364

Junior, Howard Lopes Ribeiro, E-mail: [e-mail]; Oliveira, Roberta Taiane Germano de, E-mail: [e-mail]; Paula Borges, Daniela de, E-mail: [e-mail]; Costa, Marília Braga, E-mail: [e-mail]; Farias, Izabelle Rocha, E-mail: [e-mail]; Santos, Antônio Wesley Araújo dos; Magalhães, Silvia Maria Meira, E-mail: [e-mail]; Pinheiro, Ronald Feitosa, E-mail: [e-mail], E-mail: [e-mail] ^[1]

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1. Federal University of Ceara, Cancer Cytogenomic Laboratory, Center for Research and Drug Development (NPDM) (Brazil)

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/mm{sup 3} (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. Graphic Abstract: .

• OSTI ID: 22938364
• Journal Information: Medical Oncology (Online), Vol. 36, Issue 12; Other Information: Copyright (c) 2019 Springer Science+Business Media, LLC, part of Springer Nature; http://www.springer-ny.com; Country of input: International Atomic Energy Agency (IAEA); ISSN 1559-131X
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
BIOLOGICAL PATHWAYS
CLINICAL TRIALS
DNA REPAIR
HEMOGLOBIN
NEOPLASMS
NEUTROPHILS
PATIENTS
STRAND BREAKS
THERAPY