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Ref Type Journal Article
PMID (21852505)
Authors Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT, Toretsky JA, Rosenberg SA, Shukla N, Ladanyi M, Samuels Y, James CD, Yu H, Kim JS, Waldman T
Title Mutational inactivation of STAG2 causes aneuploidy in human cancer.
Journal Science (New York, N.Y.)
Vol 333
Issue 6045
Date 2011 Aug 19
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
STAG2 E523* nonsense loss of function - predicted STAG2 E523* results in a premature truncation of the Stag2 protein at amino acid 523 of 1231 (UniProt.org). E523* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of E523 (PMID: 26871722, PMID: 21852505), E523* is predicted to lead to a loss of Stag2 protein function.
STAG2 N357fs frameshift loss of function STAG2 N357fs results in a change in the amino acid sequence of the Stag2 protein beginning at aa 357 of 1231, likely resulting in premature truncation of the functional protein (UniProt.org). N357fs results in a loss of Stag2 protein expression and defective sister chromatid cohesion and is associated with chromosomal instability in cell culture (PMID: 21852505).
STAG2 Q593* nonsense loss of function - predicted STAG2 Q593* results in a premature truncation of the Stag2 protein at amino acid 593 of 1231 (UniProt.org). Q593* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of Q593 (PMID: 26871722, PMID: 21852505), and altered cell proliferation in Q593* expressing cell lines (PMID: 29649003), Q593* is predicted to lead to a loss of Stag2 protein function.
STAG2 Q735* nonsense loss of function - predicted STAG2 Q735* results in a premature truncation of the Stag2 protein at amino acid 216 of 1231 (UniProt.org). Q735* results in aberrant Stag2 cytoplasmic localization in cultured cells (PMID: 21852505), and therefore, is predicted to lead to a loss fo Stag2 protein function.
STAG2 R604* nonsense loss of function - predicted STAG2 R604* results in a premature truncation of the Stag2 protein at amino acid 604 of 1231 (UniProt.org). R604* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of R604 (PMID: 26871722, PMID: 21852505), R604* is predicted to lead to a loss of Stag2 function.
STAG2 R614* nonsense loss of function - predicted STAG2 R614* results in a premature truncation of the Stag2 protein at amino acid 614 of 1231 (UniProt.org). R614* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of R614 (PMID: 26871722, PMID: 21852505), R614* is predicted to lead to a loss of Stag2 function.
STAG2 S419* nonsense loss of function - predicted STAG2 S419* results in a premature truncation of the Stag2 protein at amino acid 419 of 1231 (UniProt.org). S419* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of S419 (PMID: 26871722, PMID: 21852505), S419* is predicted to lead to a loss of Stag2 protein function.
STAG2 S653* nonsense loss of function STAG2 S653* results in a premature truncation of the Stag2 protein at amino acid 653 of 1231 (UniProt.org). S653* results in a loss of Stag2 protein function as demonstrated by aberrant cytoplasmic localization (PMID: 21852505), loss of interaction with cohesin complex subunits, impaired chromosome segregation during anaphase (PMID: 26871722), defective sister chromatid cohesion, and is associated with chromosomal instability in cell culture (PMID: 21852505, PMID: 26871722).
STAG2 T626fs frameshift loss of function - predicted STAG2 T626fs results in a change in the amino acid sequence of the Stag2 protein beginning at aa 626 of 1231, likely resulting in premature truncation of the functional protein (UniProt.org). T626fs has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of T626 (PMID: 26871722, PMID: 21852505), T626fs is predicted to lead to a loss of Stag2 function.
STAG2 Y594* nonsense loss of function - predicted STAG2 Y594* results in a premature truncation of the Stag2 protein at amino acid 594 of 1231 (UniProt.org). Y594* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of Y594 (PMID: 26871722, PMID: 21852505), Y594* is predicted to lead to a loss of Stag2 protein function.
STAG2 Y636* nonsense loss of function - predicted STAG2 Y636* results in a premature truncation of the Stag2 protein at amino acid 636 of 1231 (UniProt.org). Y636* has not been characterized, however, due to the effects of Stag2 truncating mutations downstream of Y636 (PMID: 26871722, PMID: 21852505), Y636* is predicted to lead to a loss of Stag2 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
STAG2 N357fs glioblastoma multiforme sensitive Rucaparib Preclinical - Cell culture Actionable In a preclinical study, a glioblastoma cell line harboring a STAG2 mutation (reported as STAG2 N357fs, PMID: 21852505), demonstrated increased sensitivity to treatment with Rubraca (rucaparib) in culture compared to isogenic cells with wild-type STAG2 (PMID: 24356817). 21852505 24356817
STAG2 S653* glioblastoma multiforme sensitive Camptothecin Preclinical - Cell culture Actionable In a preclinical study, glioblastoma cells harboring a STAG2 mutation (reported as STAG2 S653*, PMID: 21852505) demonstrated increased sensitivity to the combination of Lynparza (olaparib) and camptothecin compared to isogenic cells with wild-type STAG2 in culture (PMID: 24356817). 24356817 21852505
STAG2 S653* glioblastoma multiforme sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, a glioblastoma cell line harboring a STAG2 mutation (reported as STAG2 S653*, PMID: 21852505) demonstrated increased sensitivity to treatment with Lynparza (olaparib) in culture compared to isogenic cells with wild-type STAG2 (PMID: 24356817). 21852505 24356817
STAG2 N357fs glioblastoma multiforme sensitive Olaparib + Temozolomide Preclinical - Cell culture Actionable In a preclinical study, glioblastoma cells harboring a STAG2 mutation (reported as STAG2 N357fs, PMID: 21852505) demonstrated increased sensitivity to the combination of Lynparza (olaparib) and Temodar (temozolomide) compared to isogenic cells with wild-type STAG2 in culture (PMID: 24356817). 21852505 24356817
STAG2 N357fs glioblastoma multiforme sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, a glioblastoma cell line harboring a STAG2 mutation (reported as STAG2 N357fs, PMID: 21852505) demonstrated increased sensitivity to treatment with Lynparza (olaparib) in culture, resulting in decreased proliferation and colony formation, and increased DNA damage compared to isogenic cells with wild-type STAG2 (PMID: 24356817). 21852505 24356817
STAG2 N357fs glioblastoma multiforme sensitive Camptothecin + Olaparib Preclinical - Cell culture Actionable In a preclinical study, glioblastoma cells harboring a STAG2 mutation (reported as STAG2 N357fs, PMID: 21852505) demonstrated increased sensitivity to the combination of Lynparza (olaparib) and camptothecin compared to isogenic cells with wild-type STAG2 in culture (PMID: 24356817). 21852505 24356817
STAG2 N357fs glioblastoma multiforme sensitive Veliparib Preclinical - Cell culture Actionable In a preclinical study, a glioblastoma cell line harboring a STAG2 mutation (reported as STAG2 N357fs, PMID: 21852505) demonstrated increased sensitivity to treatment with Veliparib (ABT-888) in culture compared to isogenic cells with wild-type STAG2 (PMID: 24356817). 21852505 24356817