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.

Prognostic importance of Aurora Kinases and mitotic spindle genes transcript levels in Myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) are a heterogeneous group of clonal disease characterized by insufficiency of bone marrow, increase of apoptosis and increased risk of acute leukemia progression. Proteins related to the mitotic spindle (AURKA, AURKB, TPX2), to the mitotic checkpoint (MAD2, CDC20) and the regulation of the cell cycle (p21) are directly related to chromosomal stability and tumor development. This study aimed to evaluate the mRNA expression levels of these genes in 101 MDS patients using a real-time PCR methodology. We identified that CDC20 expression are increased in patients with dysmegakaryopoiesis (p=0.024), thrombocytopenia (p=0.000) and high-risk patients (p=0.014, 0.018) MAD2 expression are decreased in patients with 2 or 3 cytopenias (p=0.000) and neutrophil below 800/mm3. TPX2 is also overexpressed in patients presenting dysmegakaryopoiesis (p=0.009). A decrease in AURKA and AURKB expression were observed in patients with altered karyotype (p=0.000), who presented dysplasia in 3 lineages (p=0.000; 0.017) and hemoglobin inferior to 8g/dL (p=0.024). The expression of AURKA, AURKB and MAD2 (p=0.000; 0.001; 0.025) were decreased in patients with hypoplastic MDS, associated with high frequency of chromosomal alterations and high mortality rate. This study reaffirms the importance of aurora kinases and mitotic spindle genes to the pathogenesis and clinical evolution of MDS.