title: GSTT1 copy number gain and ZNF overexpression are predictors of poor response to imatinib in gastrointestinal stromal tumors.
abstract: Oncogenic mutations in gastrointestinal stromal tumors (GISTs) predict prognosis and therapeutic responses to imatinib. In wild-type GISTs, the tumor-initiating events are still unknown, and wild-type GISTs are resistant to imatinib therapy. We performed an association study between copy number alterations (CNAs) identified from array CGH and gene expression analyses results for four wild-type GISTs and an imatinib-resistant PDGFRA D842V mutant GIST, and compared the results to those obtained from 27 GISTs with KIT mutations. All wild-type GISTs had multiple CNAs, and CNAs in 1p and 22q that harbor the SDHB and GSTT1 genes, respectively, correlated well with expression levels of these genes. mRNA expression levels of all SDH gene subunits were significantly lower (P≤0.041), whereas mRNA expression levels of VEGF (P=0.025), IGF1R (P=0.026), and ZNFs (P<0.05) were significantly higher in GISTs with wild-type/PDGFRA D842V mutations than GISTs with KIT mutations. qRT-PCR validation of the GSTT1 results in this cohort and 11 additional malignant GISTs showed a significant increase in the frequency of GSTT1 CN gain and increased mRNA expression of GSTT1 in wild-type/PDGFRA D842V GISTs than KIT-mutant GISTs (P=0.033). Surprisingly, all four malignant GISTs with KIT exon 11 deletion mutations with primary resistance to imatinib had an increased GSTT1 CN and mRNA expression level of GSTT1. Increased mRNA expression of GSTT1 and ZNF could be predictors of a poor response to imatinib. Our integrative approach reveals that for patients with wild-type (or imatinib-resistant) GISTs, attempts to target VEGFRs and IGF1R may be reasonable options.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Eui Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: Guhyun
authors.initials: G
authors.lastname: Kang
authors.forename: Shin Woo
authors.initials: SW
authors.lastname: Kang
authors.forename: Kee-Taek
authors.initials: KT
authors.lastname: Jang
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.forename: Cheol Keun
authors.initials: CK
authors.lastname: Park
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Sohn
authors.forename: Sung
authors.initials: S
authors.lastname: Kim
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002878:Chromosomes, Human, Pair 1; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase