Open AccessPrognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis
Author(s) -
Ichikawa Hiroshi,
Yoshida Akihiko,
Kanda Tatsuo,
Kosugi Shinichi,
Ishikawa Takashi,
Hanyu Takaaki,
Taguchi Takahiro,
Sakumoto Marimu,
Katai Hitoshi,
Kawai Akira,
Wakai Toshifumi,
Kondo Tadashi
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12565
Subject(s) - gist , malignancy , stromal tumor , transcriptome , hazard ratio , immunohistochemistry , stromal cell , proportional hazards model , biomarker , oncology , cancer research , clinical significance , acute promyelocytic leukemia , medicine , biology , pathology , gene expression , gene , retinoic acid , confidence interval , genetics
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.