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Three Classes of Genes Mutated In Colorectal Cancers with Chromosomal Instability

¹ Sidney Kimmel Comprehensive Cancer Center and Howard Hughes Medical Institute at Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Howard Hughes Medical Institute, Department of Medicine and Ireland Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio; ³ Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York; and ⁴ Centre National de la Recherche Scientifique, Centre de Génétique Moléculaire, Gif-sur-Yvette, France

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.

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