title: Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability.
abstract: OBJECTIVE
  Several lines of evidence indicate that axon guidance genes are involved not only in neural development but also in cancer development. ROBO1 and ROBO2, crucial regulators of axon guidance, are considered potential tumour suppressor genes. The aim of this study was to explore whether ROBO1 and ROBO2 genes are somatically mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC).
  
  
  METHODS
  In a public database, we observed that both ROBO1 and ROBO2 had mononucleotide repeats in their coding exons that could be mutation targets in cancers with microsatellite instability (MSI). We analysed mutations of these repeats in 77 GC and 88 CRC either with high MSI (MSI-H) or low MSI/microsatellite stability (MSI-L/MSS) by single-strand conformation polymorphism (SSCP) and DNA sequencing. We analysed ROBO1 and ROBO2 expressions in GC and CRC by immunohistochemistry as well.
  
  
  RESULTS
  Overall, we found five ROBO1 and five ROBO2 frameshift mutations in the repeats. They were detected exclusively in the cancers with MSI-H (10/70, 14.2%), but not in MSI-L/MSS (0/95, 0%) (p=0.018). In the immunohistochemistry, loss of ROBO2 expression was identified in 22 (29%) and 17 (19%) of GC and CRC, respectively, while increased expression of ROBO2 was found in 15 (20%) and 22 (25%) of GC and CRC, respectively. There were co-occurrences of mutation and loss of expression in both ROBO1 (4/5, 80% mutated cases, p<0.001) and ROBO2 (5/5, 100% mutated cases, p<0.05) genes.
  
  
  CONCLUSIONS
  This is the first report of ROBO1 and ROBO2 frameshift mutations in GC and CRC. Frameshift mutations of ROBO1 and ROBO2 genes and alteration of ROBO2 expression in GC and CRC suggest that both genes might play roles in the pathogenesis of GC and CRC.
authors.affiliation: Department of Pathology and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Je
authors.forename: Min
authors.initials: M
authors.lastname: Gwak
authors.forename: Hyerim
authors.initials: H
authors.lastname: Oh
authors.forename: Mi Ryoung
authors.initials: MR
authors.lastname: Choi
authors.forename: Youn Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; C498890:ROBO2 protein, human