Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group

被引:29
作者
Monument, Michael J. [1 ,2 ]
Johnson, Kirsten M. [2 ]
McIlvaine, Elizabeth [3 ]
Abegglen, Lisa [2 ]
Watkins, W. Scott [4 ,5 ]
Jorde, Lynn B. [4 ,5 ]
Womer, Richard B. [6 ]
Beeler, Natalie [7 ]
Monovich, Laura [7 ]
Lawlor, Elizabeth R. [8 ,9 ]
Bridge, Julia A. [10 ]
Schiffman, Joshua D. [2 ,11 ]
Krailo, Mark D. [3 ]
Randall, R. Lor [1 ,2 ]
Lessnick, Stephen L. [1 ,2 ,11 ]
机构
[1] Univ Utah, Dept Orthoped Surg, Sarcoma Serv, Salt Lake City, UT 84112 USA
[2] Univ Utah, Ctr Childrens Canc Res, Huntsman Canc Inst, Salt Lake City, UT USA
[3] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA
[4] Univ Utah, Dept Human Genet, Salt Lake City, UT USA
[5] Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT USA
[6] Univ Penn, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
[7] Nationwide Childrens Hosp, Res Inst, Childrens Oncol Grp, Biopathol Ctr, Columbus, OH USA
[8] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA
[9] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[10] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Nebraska Med Ctr, Omaha, NE USA
[11] Univ Utah, Div Pediat Hematol Oncol, Salt Lake City, UT USA
来源
PLOS ONE | 2014年 / 9卷 / 08期
关键词
ROUND-CELL TUMORS; EWS/FLI; INSTABILITY; GENE; SPECIFICITY; ONCOPROTEIN; EXPRESSION; SEQUENCES; ELEMENTS; FAMILY;
D O I
10.1371/journal.pone.0104378
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite. Objectives: Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes. Results: A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes. Conclusions: These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.
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页数:14
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