Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers

Thomas D. Barber, Kirk McManus, Karen W.Y. Yuen, Marcelo Reis, Giovanni Parmigiani, Dong Shen, Irene Barrett, Yasaman Nouhi, Forrest Spencer, Sanford Markowitz, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, Christoph Lengauer, Philip Hieter

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3443-3448
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number9
DOIs
StatePublished - Mar 4 2008

Keywords

  • CDC4
  • MRE11A
  • Somatic mutation

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers'. Together they form a unique fingerprint.

Cite this