title: Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.
abstract: Although the majority of colorectal cancers exhibit chromosome instability (CIN), only a few genes that might cause this phenotype have been identified and no general mechanism underlying their function has emerged. To systematically identify somatic mutations in potential CIN genes in colorectal cancers, we determined the sequence of 102 human homologues of 96 yeast CIN genes known to function in various aspects of chromosome transmission fidelity. We identified 11 somatic mutations distributed among five genes in a panel that included 132 colorectal cancers. Remarkably, all but one of these 11 mutations were in the homologs of yeast genes that regulate sister chromatid cohesion. We then demonstrated that down-regulation of such homologs resulted in chromosomal instability and chromatid cohesion defects in human cells. Finally, we showed that down-regulation or genetic disruption of the two major candidate CIN genes identified in previous studies (MRE11A and CDC4) also resulted in abnormal sister chromatid cohesion in human cells. These results suggest that defective sister chromatid cohesion as a result of somatic mutations may represent a major cause of chromosome instability in human cancers.
authors.affiliation: The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Barber
authors.forename: Kirk
authors.initials: K
authors.lastname: McManus
authors.forename: Karen W Y
authors.initials: KW
authors.lastname: Yuen
authors.forename: Marcelo
authors.initials: M
authors.lastname: Reis
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Irene
authors.initials: I
authors.lastname: Barrett
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Nouhi
authors.forename: Forrest
authors.initials: F
authors.lastname: Spencer
authors.forename: Sanford
authors.initials: S
authors.lastname: Markowitz
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics; D002842:Chromatids; D043171:Chromosomal Instability / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005800:Genes, Fungal; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C121766:MRE11 protein, human; C487465:NIPBL protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C492318:SMC3 protein, human; C406153:STAG3 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1; C506646:RNF20 protein, human; D044767:Ubiquitin-Protein Ligases; D000076228:MRE11 Homologue Protein