title: 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.
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Chun-Kang
authors.initials: CK
authors.lastname: Chang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Shi
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: You-Shan
authors.initials: YS
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Shu-Cheng
authors.initials: SC
authors.lastname: Gu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Fei
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Su
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Lu-Xi
authors.initials: LX
authors.lastname: Song
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
mesh_terms: D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D018450:Disease Progression; D059472:Exome; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C498890:ROBO2 protein, human