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

Feng Xu, Ling-Yun Wu, Chun-Kang Chang, Qi He, Zheng Zhang, Li Liu, Wen-Hui Shi, Juan Guo, Yang Zhu, You-Shan Zhao, Shu-Cheng Gu, Cheng-Ming Fei, Dong Wu, Li-Yu Zhou, Ji-Ying Su, Lu-Xi Song, Chao Xiao and Xiao Li ()
Additional contact information
Feng Xu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Ling-Yun Wu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Chun-Kang Chang: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Qi He: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Zheng Zhang: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Li Liu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Wen-Hui Shi: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Juan Guo: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Yang Zhu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
You-Shan Zhao: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Shu-Cheng Gu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Cheng-Ming Fei: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Dong Wu: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Li-Yu Zhou: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Ji-Ying Su: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Lu-Xi Song: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Chao Xiao: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
Xiao Li: Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9806

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