Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers

doi:10.1073/pnas.0712384105

Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers

*The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231;
^‡Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, Canada V6T 1Z4;
^§Departments of Biostatistics and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231;
^¶McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
^‖Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland, OH 44106

Contributed by Bert Vogelstein, January 4, 2008 (received for review December 11, 2007)

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.

Footnotes

**To whom correspondence may be addressed. E-mail: vogelbe{at}jhmi.edu or hieter{at}msl.ubc.ca
Author contributions: T.D.B., K.M., and K.W.Y.Y. contributed equally to this work; T.D.B., K.M., K.W.Y.Y., F.S., V.E.V., K.W.K., B.V., C.L., and P.H. designed research; T.D.B., K.M., K.W.Y.Y., M.R., D.S., I.B., Y.N., and C.L. performed research; S.M. contributed new reagents/analytic tools; T.D.B., K.M., K.W.Y.Y., M.R., G.P., D.S., I.B., Y.N., F.S., V.E.V., K.W.K., B.V., C.L., and P.H. analyzed data; and T.D.B., K.M., K.W.Y.Y., G.P., F.S., S.M., V.E.V., K.W.K., B.V., C.L., and P.H. wrote the paper.
↵ ^†Present address: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
↵ ^††Present address: Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0712384105/DC1.