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

AbstractCancer-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 axisBRCA1-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 ofLIG4 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...
Source: Medical Oncology - Category: Cancer & Oncology Source Type: research