Abstract 5301: Integrated array CGH and expression profiling revealed candidate biomarkers in gastrointestinal stromal tumors.
Authors: Kang Guhyun , Lee Eui Jin , Kang Shin Woo , Jang Kee-Taek , Lee Jeeyun , Park Joon Oh , Park Cheol Keun , Sohn Tae Sung , Kim Sung , Do In-Gu , Kim Kyoung-Mee , Corless Christopher L. 
Published: August 2014

Oncogenic KIT and PDGFRA mutations play an important role in the development of some, but not all, gastrointestinal stromal tumors (GISTs). Other chromosomal alterations are involved in the clinical progression of these cancers, but these have not been well defined. We studied the association between copy number alterations (CNAs) and gene expression in 32 GISTs, including 4 wild type tumors, using array CGH and gene expression analyses.

All tumors exhibited multiple CNAs and significant numbers of novel recurrent regions were identified in wild type GISTs. Among them, a significant correlation with the corresponding expression between wild type and mutant GISTs was observed in 1p and 22q, which harbor SDHB and GSTT1 genes, respectively. All 7 GISTs with copy number losses on 1p36.33-p11.2 showed loss of heterozygosity in at least one of 3 microsatellite markers in the SDHB gene. Loss of SDH complex activity in GISTs can result in increased level of HIF1, which activates the transcription of VEGF and IGF2. In this study, VEGF (2.31-fold increase, P=0.025) and IGF1R (2.76-fold increase, P=0.062) expression levels were higher in wild type/PDGFRA D842V GISTs compared to KIT-mutant GISTs. As constituents of the MAPK cascade, mRNA levels of BRAF (0.50-fold increase, P=0.001) and its downstream effector, MYC (2.21-fold increase, P=0.017) were also increased in wild type/PDGFRA D842V GISTs. For GSTT1, qRT-PCR on all 32 GISTs in this cohort and 22 additional malignant GISTs showed significantly frequent gains of GSTT1 copy number in wild type/PDGFRA D842V GISTs compared to KIT-mutant GISTs (91.7% vs. 54.8%; P=0.03). Gains of GSTT1 copy number correlated positively with mRNA expression by qRT-PCR (r=0.705, P &lt;0.001). Unexpectedly, all four patients with malignant GISTs in the small intestine and KIT exon 11 deletion mutations showing primary resistance to imatinib showed increased copy numbers and mRNA expression of GSTT1.

Our integrative approach reveals that for the patients with wild type (or imatinib-resistant) GISTs, attempts to target IGF1R and VEGFR2 would seem to be reasonable options. Moreover, copy number analysis of GSTT1 may be an effective tool to predict imatinib response, and hence help select the best drug and an optimal dose. Further large-scale and well-designed clinical studies are warranted to validate our findings.

Citation Format: Guhyun Kang, Eui Jin Lee, Shin Woo Kang, Kee-Taek Jang, Jeeyun Lee, Joon Oh Park, Cheol Keun Park, Tae Sung Sohn, Sung Kim, In-Gu Do, Kyoung-Mee Kim, Christopher L. Corless. Integrated array CGH and expression profiling revealed candidate biomarkers in gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5301. doi:10.1158/1538-7445.AM2013-5301