Prognostic significance of promyelocytic leukemia expression in gastrointestinal stromal tumor; integrated proteomic and transcriptomic analysis

Hiroshi Ichikawa, Akihiko Yoshida, Tatsuo Kanda, Shin-ichi Kosugi, Takashi Ishikawa, Takaaki Hanyu, Takahiro Taguchi, Marimu Sakumoto, Hitoshi Katai, Akira Kawai, Toshifumi Wakai, Tadashi Kondo
2014 Cancer Science  
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
more » ... n 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. G astrointestinal stromal tumors (GIST) are a common type of soft-tissue sarcoma. (1) Approximately 75-80% of GIST harbor an activating mutation in the KIT oncogene and 5-8% in platelet-derived growth factor receptor-a (PDGFRA), which are both key molecular drivers of GIST pathogenesis. (2) (3) (4) (5) Adjuvant therapy with imatinib, a tyrosine kinase inhibitor, prolongs recurrence-free survival (RFS) after complete resection. (6,7) Recently, a randomized trial revealed that patients with a high-risk of recurrence show longer survival with 3 years of imatinib administration than with 1 year. (8) Almost all patients receiving imatinib therapy suffer some adverse effects, and approximately 50% of the operative GIST patients are cured by surgery alone. (8) Therefore, prognostic markers are needed to optimize adjuvant imatinib therapy. (9) Gastrointestinal stromal tumor arise predominantly in the stomach (60-70%) and small intestine (20-30%). (10) GIST of the small intestine (I-GIST) show more aggressive behavior than those of the stomach (S-GIST), with similar size and mitotic activity. (11) Therefore, the tumor site is included as a factor in currently employed risk stratification schemes. (12) Investigations of genetic aberrations that are specific to tumors arising at certain anatomical sites can provide clues to understanding the molecular mechanisms of malignant behavior of GIST, thus leading to the development of prognostic biomarkers. It has been reported that differences in expression or mutation of KIT and PDGFRA are associated with the tumor site. (13, 14) In addition, chromosomal aberrations and gene expressions that are specific to I-GIST have been identified in genome-wide global studies, and these have also been shown to be adverse prognostic factors. (15) (16) (17) (18) (19) (20) However, these reports lack validation studies for the confirmation of the prognostic value and clinical utility. Therefore, intensive validation studies, including multi-institutional research, are needed to establish the prognostic biomarkers from tumor site-specific genes. In the present study, we aimed to identify the molecular backgrounds specific to the tumor site and to discover the prognostic biomarker in GIST. We integrated proteomic and transcriptomic analysis, and observed a total of 2555 genes. For the proteomic analysis, we applied a label-free proteomics, allowing comprehensive analysis of thousands of proteins
doi:10.1111/cas.12565 pmid:25457157 pmcid:PMC4317774 fatcat:yte4hof2cjdnhcshs4s2bfqoam