Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes

Abstract

The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.

Differential expression levels and methylation status of ROBO1 in mantle cell lymphoma and chronic lymphocytic leukaemia

“…ROBO1 has in a single study been suggested as a progression-related driver in myelodysplastic syndromes, which supports the idea that the gene is a co-player in progression of haematological neoplasms [12]. In the current study, we identified two AML patients with medium expression of the gene.…”

Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites

“…Stored simultaneous bone marrow aspirates were not available for the cases in the present study. Review of the literature revealed that five genes listed in Table have been reported to be downregulated in the bone marrow in percentages of AML patients: CDH1 , ID4 , ITIH5 , ROBO1 , and SFRP1 . The percentage of cases with downregulation, by methylation in the majority, varied from 14% to 63% and survival was noted to be poor among these cases.…”

TP53 mutations predict decitabine‐induced complete responses in patients with myelodysplastic syndromes

“…Genomic DNA was isolated using a TIANamp Genomic DNA Kit (TIANGEN, Beijing, China), according to the manufacturer's instructions. Next‐generation sequencing was carried out for 28 genes using a MiSeq Benchtop Sequencer (Illumina, San Diego, CA, USA), as previously reported (Xu et al , ). These genes were found to exhibit recurrent mutations via previous whole‐exome sequencing and were also related to cancer development.…”