title: Mutational inactivation of STAG2 causes aneuploidy in human cancer.
abstract: 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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC 20057, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Solomon
authors.forename: Taeyeon
authors.initials: T
authors.lastname: Kim
authors.forename: Laura A
authors.initials: LA
authors.lastname: Diaz-Martinez
authors.forename: Joshlean
authors.initials: J
authors.lastname: Fair
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Brent T
authors.initials: BT
authors.lastname: Harris
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Neerav
authors.initials: N
authors.lastname: Shukla
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
mesh_terms: D000782:Aneuploidy; D034961:Antigens, Nuclear / Q000235:genetics* / Q000502:physiology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002842:Chromatids / Q000502:physiology; D043171:Chromosomal Instability; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018390:Gene Targeting; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D008297:Male; D008545:Melanoma / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012512:Sarcoma, Ewing / Q000235:genetics; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; C508565:STAG2 protein, human; D000097722:Cohesins