PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival
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Chien-Feng Li1,2,3,8, Ting-Ting Liu4, I-Chieh Chuang4,8, Yen-Yang Chen5, Fu-Min Fang6, Ti-Chun Chan1, Wan-Shan Li7,8, Hsuan-Ying Huang4,8
1Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
2National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
3Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
4Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
5Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
6Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
7Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
8Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan
Hsuan-Ying Huang, email: [email protected]
Keywords: metabolism, lipid catabolism, PLCB4, transcriptome, GIST
Abbreviations: GIST, gastrointestinal stromal tumor; NIH, National Institute of Health; NCCN, National Comprehensive Cancer Network; PLCB4, phospholipase C-ß4.
Received: October 09, 2016 Accepted: December 08, 2016 Published: February 13, 2017
To explore the implications of lipid catabolism-associated genes in gastrointestinal stromal tumors, we reappraised transcriptomic and genomic datasets and identified copy-gained and differentially upregulated PLCB4 gene associated with tumor progression. On full sections, PLCB4 mRNA abundance and PLCß4 immunoexpression were validated in 70 cases. On tissue microarrays, PLCB4 gene copies and PLCß4 immunoexpression were both informative in 350 cases with KIT/PDGFRA/BRAF genotypes noted in 213. In GIST48 cell line, we stably silenced PLCB4 and YAP1 to characterize their functional effects and regulatory link. Compared with normal tissue, PLCB4 mRNA abundance significantly increased across tumors of various risk levels (p<0.001), and was strongly correlated with immunoexpression level (p<0.001, r=0.468). Including polysomy (12.6%) and amplification (17.4%), PLCB4 copy gain was detected in 105 (30%) cases and significantly more frequent (p<0.001) in cases exhibiting higher PLCß4 immunoexpression (82/175). Copy gain and protein overexpression were modestly associated with unfavorable genotypes (both p<0.05), strongly associated with increased size, mitosis, and risk levels defined by both the NIH and NCCN schemes (all p<0.001), and univariately predictive of shorter disease-free survival (both p<0.0001). In PLCß4-overexpressing cases, PLCB4 copy gain still predicted worse prognosis (p<0.0001). In a multivariate comparison, both overexpression (p=0.007, hazard ratio: 2.454) and copy gain (p=0.031, hazard ratio: 1.892) exhibited independent impact. In vitro, YAP1 increased PLCB4 mRNA and protein expression, and both molecules significantly promoted cell proliferation. Being driven by copy gain or YAP1, PLCß4 is a novel overexpressed enzyme regulating lipid catabolism that promotes cell proliferation and independently confers a worse prognosis.
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