title: Prognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis.
abstract: Prognostic markers are urgently needed to optimize the postoperative treatment strategies for gastrointestinal stromal tumors (GIST). GIST of the small intestine (I-GIST) show more aggressive behavior than those of the stomach (S-GIST), and the molecular background of the malignancy in I-GIST may include potential prognostic biomarkers. We conducted integrated proteomic and transcriptomic analysis to identify genes showing differential expressions according to the tumor site. We generated protein expression profiles for four cases each of surgically resected I-GIST and S-GIST using label-free proteomic analysis. For proteins showing differential expressions, global mRNA expression was compared between 9 I-GIST and 23 S-GIST. Among the 2555 genes analyzed, we found that promyelocytic leukemia (PML), a tumor suppressor gene, was significantly downregulated in I-GIST at both the protein and mRNA levels (P < 0.01; fold difference ≥2.0). Immunohistochemistry of 254 additional cases from multiple clinical facilities showed that PML-negative cases were significantly frequent in the I-GIST group (P < 0.001). The 5-year recurrence-free survival rate was significantly lower in the PML-negative than in the PML-positive cases (60.1% vs 91.7%; P < 0.001). Multivariate analysis revealed that downregulation of PML was an independent unfavorable prognostic factor (hazard ratio = 2.739; P = 0.001). Our study indicated that prognostication based on PML expression may have potential for optimizing the treatment strategy for GIST patients. Further validation studies of PML for clinical application, and investigation for the mechanistic significance of PML to clarify the molecular backgrounds of malignancy in GIST are warranted.
authors.affiliation: Division of Pharmacoproteomics, National Cancer Center Research Institute, Tokyo, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Kosugi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hanyu
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Marimu
authors.initials: M
authors.lastname: Sakumoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Katai
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D000071156:Promyelocytic Leukemia Protein; D016016:Proportional Hazards Models; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020543:Proteome; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human
keywords: Gastrointestinal stromal tumor; promyelocytic leukemia; proteomics; transcriptomics; tumor site