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/mm(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.