Reference Detail

Ref Type

Journal Article

PMID

(26936505)

Authors

Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D, Mendez F, Kamran N, Dzaman M, Mulpuri L, Krasinkiewicz J, Doherty R, Lemons R, Brosnan-Cashman JA, Li Y, Roh S, Zhao L, Appelman H, Ferguson D, Gorbunova V, Meeker A, Jones C, Lowenstein PR, Castro MG

Title

ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	8	328	2016 Mar 2	328ra28	Sci Transl Med

URL

Abstract Text

Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
ATRX	NCBI	JMS\|MRX52\|RAD54\|RAD54L\|XH2\|XNP\|ZNF-HX		ATRX, ATRX chromatin remodeler, is in the SWI/SNF family of chromatin remodeling proteins and plays a role in DNA repair and telomere length (PMID: 36894374). ATRX loss and mutations have been identified in a high percentage of tumor types including glioma (PMID: 23249563; PMID: 26936505, PMID: 31908895) and copy number loss has also been observed in pancreatic neuroendocrine tumors (PMID: 30081149) and ovarian ependymomas (PMID: 29944970).	Tumor suppressor

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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATRX loss	glioblastoma	sensitive	Topotecan	Preclinical	Actionable	In a preclinical study, loss of ATRX sensitized glioblastoma cell lines to double-stranded DNA-damaging agents, including Adriamycin (doxorubicin), Topotecan, and Camptosar (irinotecan) in culture (PMID: 26936505).	26936505
ATRX loss	glioblastoma	sensitive	Irinotecan	Preclinical	Actionable	In a preclinical study, loss of ATRX sensitized glioblastoma cell lines to double-stranded DNA-damaging agents, including Adriamycin (doxorubicin), Topotecan, and Camptosar (irinotecan) in culture (PMID: 26936505).	26936505
ATRX loss	glioblastoma	sensitive	Doxorubicin	Preclinical	Actionable	In a preclinical study, loss of ATRX sensitized glioblastoma cell lines to double-stranded DNA-damaging agents, including Adriamycin (doxorubicin), Topotecan, and Camptosar (irinotecan) in culture (PMID: 26936505).	26936505