title: Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer.
abstract: OBJECTIVE
  To examine whether chromosomal instability (CIN) phenotype, determined by the severity of CIN, can predict survival for stages II and III colorectal cancer (CRC).
  
  
  METHODS
  We determined microsatellite instability (MSI) and loss of heterozygosity (LOH) status in 1,103 patients (training [n = 845] and validation [n = 258] sets with stages II and III CRC). The LOH ratio was defined as the frequency of LOH in chromosomes 2p, 5q, 17p, and 18q. According to the LOH ratio, non-MSI high tumors were classified as CIN high (LOH ratio ≥ 33%) or CIN low (LOH ratio < 33%). CIN-high tumors were subclassified as CIN high (mild type; LOH ratio < 75%) or CIN high (severe type; LOH ratio ≥ 75%). We used microarrays to identify a gene signature that could classify the CIN phenotype and evaluated its ability to predict prognosis.
  
  
  RESULTS
  CIN high showed the worst survival (P < .001), whereas there was no significant difference between CIN low and MSI high. CIN high (severe type) showed poorer survival than CIN high (mild type; P < .001). Multivariate analysis revealed that CIN phenotype was an independent risk factor for disease-free and overall survival, respectively, in both the training (P < .001 and P = .0155) and validation sets (P < .001 and P = .0076). Microarray analysis also revealed that survival was significantly poorer in those with the CIN-high than in the CIN-low gene signature (P = .0203). In a validation of 290 independent CRCs (GSE14333), the CIN-high gene signature showed significantly poorer survival than the CIN-low signature (P = .0047).
  
  
  CONCLUSIONS
  The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC.
authors.affiliation: Department of Surgical Oncology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. toshwatanabe@yahoo.co.jp
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobunai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Matsuda
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ishihara
authors.forename: Keijiro
authors.initials: K
authors.lastname: Nozawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamada
authors.forename: Tamuro
authors.initials: T
authors.lastname: Hayama
authors.forename: Eisuke
authors.initials: E
authors.lastname: Inoue
authors.forename: Junko
authors.initials: J
authors.lastname: Tamura
authors.forename: Hisae
authors.initials: H
authors.lastname: Iinuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Tetsuichiro
authors.initials: T
authors.lastname: Muto
mesh_terms: D000368:Aged; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008969:Molecular Sequence Data; D010641:Phenotype; D011379:Prognosis