Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles

被引:117
作者
Subramanian, S
West, RB
Corless, CL
Ou, WB
Rubin, BP
Chu, KM
Leung, SY
Yuen, ST
Zhu, S
Hernandez-Boussard, T
Montgomery, K
Nielsen, TO
Patel, RM
Goldblum, JR
Heinrich, MC
Fletcher, JA
van de Rijn, M
机构
[1] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA
[2] Oregon Hlth & Sci Univ, OHSU Canc Inst, Dept Pathol, Portland, OR 97201 USA
[3] Portland VA Med Ctr, Portland, OR USA
[4] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Boston, MA USA
[6] Univ Washington, Med Ctr, Dept Anat Pathol, Seattle, WA 98195 USA
[7] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China
[8] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[9] Stanford Univ, Med Ctr, Dept Biochem, Stanford, CA 94305 USA
[10] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada
[11] Vancouver Gen Hosp, Genet Pathol Evaluat Ctr, Vancouver, BC, Canada
[12] Cleveland Clin Fdn, Dept Anat Pathol, Cleveland, OH 44195 USA
[13] Oregon Hlth & Sci Univ, OHSU Canc Inst, Dept Med, Portland, OR 97201 USA
关键词
GIST; KIT; PDGFRA; mutations; microarray; gene expression;
D O I
10.1038/sj.onc.1208056
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.
引用
收藏
页码:7780 / 7790
页数:11
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