title: PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival.
abstract: 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.
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: I-Chieh
authors.initials: IC
authors.lastname: Chuang
authors.affiliation: Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yen-Yang
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Ti-Chun
authors.initials: TC
authors.lastname: Chan
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Wan-Shan
authors.initials: WS
authors.lastname: Li
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D049109:Cell Proliferation; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D054799:Phospholipase C beta / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D015996:Survival Rate; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C518042:PLCB4 protein, human; D054799:Phospholipase C beta
keywords: GIST; PLCB4; lipid catabolism; metabolism; transcriptome