Journal
SCIENCE
Volume 333, Issue 6045, Pages 1039-1043Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1203619
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Funding
- NIH [R01CA115699, R21CA143282]
- SPORE grant [CA097257]
- American Cancer Society [RSG0619101]
- National Human Genome Research Institute, NIH
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Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.
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