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Pfetin, as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics

Pfetin, as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics. Yoshiyuki Suehara 1 3 4 , Kunihiko Seki 2 , Kiyonaga Fujii 1 , Tadashi Hasegawa 2 , Tadakazu Shimoda 2 , Yasuo Beppu 4 , Akira Kawai 4 , Setsuo Hirohashi 1 , Tadashi Kondo 1.

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Pfetin, as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics

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  1. Pfetin, as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics Yoshiyuki Suehara1 3 4, Kunihiko Seki2, Kiyonaga Fujii1, Tadashi Hasegawa2 , Tadakazu Shimoda2, Yasuo Beppu4, Akira Kawai4, Setsuo Hirohashi 1,Tadashi Kondo1 1. Proteome Bioinformatics Project, National Cancer Center Research Institute, Tokyo, Japan 2. Clinical Laboratory Division, National Cancer Center Research Hospital, Tokyo, Japan 3. Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan 4. Orthopedic Surgery Division, National Cancer Center Hospital, Tokyo, Japan

  2. Procedure of Proteomics Study Surgical Specimen Mass Spectrometry Data-Mining Protein spots were identified High-speed/-throughput 1D-RP mLC/NSI-MS/MS Analysis 2D-Image MW (KDa) 80 56 36 30 Protein was extracted and labeled with CyDye 1500-2000 spots 18 pH 4.0 pH 7.0 Isoelectric focusing

  3. Back Ground (GISTs) The aim of this study is to develop prognostic biomarkers for GISTs, by means of proteomic approach, and identify high-risk patients who would need further adjuvant treatment such as imatinib. • GISTs are the most common primary mesenchymal tumor of the digestive tract. • It is genetically characterized by the presence of mutations and overexpression of KIT and, clinically, characterized by their significant response to treatment with imatinib. • However, there are certain populations of patients who can be treated only by simple resection and do not need imatinib treatment.

  4. Strategy Identify the informative spots Confirmed these results Western-blot, Immunochemical study Verified the power of biomarker Large-scale sample set (Immunohistochemical study) “Good prognosis GISTs” = No-metastasis over 2 years Low or IM Risk group * (9 samples) “Poor prognosis GISTs” = Metastasis within 1 year (8 samples) vs ＊Pathological factors(Risk Classification-> Hasegawa T. et al: Human Pathology. 2002)

  5. Cluster Analysis 43 spots (p < 0.01) Pfetin 1513 spots 43 spots Wilcoxon test Poor-prognosis GISTs Good-prognosis GISTs Poor-prognosis GISTs Metastasis within 1 year (samples 1-8) Good-prognosis GISTs No-metastasis over 2 years Low or IM Risk group (samples 9-17)

  6. Western Blotting (Pfetin antibody) Good prognosis GISTs Poor prognosis GISTs (Pfetin antibody) Immunohistochemical study Good prognosis GISTs Poor prognosis GISTs

  7. 5-year: 93.9% 5-year: 36.2% Metastasis-Free Survival of the M0 GISTs Patients According to the Expression of Pfetin (NCC :210 cases) (Immunohistochemical Study) P < 0.0001 210 cases, M0, primary samples Suehara Y et al. Clin Cancer Res (2008) 14: 1707-1717 Nature Clinical Practice Oncology (2008) 5, 364-365

  8. 5-year: 97.2% 5-year: 76.5% 210 cases, M0, primary samples P < 0.0001 Overall Survival of the M0 GISTs Patients According to the Expression of Pfetin (NCC :210 cases) (Immunohistochemical Study) Suehara Y et al. Clin Cancer Res (2008) 14: 1707-1717 Nature Clinical Practice Oncology (2008) 5, 364-365

  9. Metastasis-Free Survival Curve of GISTs According to Risk Classification (NCC :210 cases) N=46 N=110 N=54 Low risk Intermediate risk High risk Suehara Y et al. Clin Cancer Res (2008) 14: 1707-1717 Nature Clinical Practice Oncology (2008) 5, 364-365

  10. Metastasis-Free Survival Curve of GISTs According to Pfetin Immunochemical Stain (NCC :210 cases) Low risk Intermediate risk Pfetin positive (N=100) Pfetin positive (N=44) Pfetin negative (N=2) Pfetin negative (N=10) N=46 N=110 P=0.0109 P<0.0001 High risk Pfetin positive (N=27) P = 0.0002 Pfetin negative (N=27) N=54 P=0.0002 Suehara Y et al. Clin Cancer Res (2008) 14: 1707-1717 Nature Clinical Practice Oncology (2008) 5, 364-365

  11. Multivariate Analysis of Metastasis Free Survival by Cox Regression

  12. Conclusion • We examined the proteomic profile of GISTs according to prognosis using both 2D-DIGE and clinical data. • Pfetin expression was a significant predictor for metastasis and survival of patients with GISTs. • Pfetin can be a strong candidate for a biomarker to predict the metastasis in GISTs patients.

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