title: Three classes of genes mutated in colorectal cancers with chromosomal instability.
abstract: Although most colorectal cancers are chromosomally unstable, the basis for this instability has not been defined. To determine whether genes shown to cause chromosomal instability in model systems were mutated in colorectal cancers, we identified their human homologues and determined their sequence in a panel of colorectal cancers. We found 19 somatic mutations in five genes representing three distinct instability pathways. Seven mutations were found in MRE11, whose product is involved in double-strand break repair. Four mutations were found among hZw10, hZwilch/FLJ10036, and hRod/KNTC, whose products bind to one another in a complex that localizes to kinetochores and controls chromosome segregation. Eight mutations were found in Ding, a previously uncharacterized gene with sequence similarity to the Saccharomyces cerevisiae Pds1, whose product is essential for proper chromosome disjunction. This analysis buttresses the evidence that chromosomal instability has a genetic basis and provides clues to the mechanistic basis of instability in cancers.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center and Howard Hughes Medical Institute at Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Cummins
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Jallepalli
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
authors.forename: Giovanni
authors.initials: G
authors.lastname: Traverso
authors.forename: Mark
authors.initials: M
authors.lastname: Awad
authors.forename: Natalie
authors.initials: N
authors.lastname: Silliman
authors.forename: Janine
authors.initials: J
authors.lastname: Ptak
authors.forename: Steve
authors.initials: S
authors.lastname: Szabo
authors.forename: James K V
authors.initials: JK
authors.lastname: Willson
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Michael L
authors.initials: ML
authors.lastname: Goldberg
authors.forename: Roger
authors.initials: R
authors.lastname: Karess
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation; D063150:Polycomb Repressive Complex 1
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D063150:Polycomb Repressive Complex 1; C080355:RING1 protein, human; D000076228:MRE11 Homologue Protein