Pfetin, as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics Yoshiyuki Suehara 1 3 4, Kunihiko Seki 2, Kiyonaga Fujii 1,

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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 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

MW(KDa) Isoelectric focusing pH 4.0 pH 7.0 Procedure of Proteomics Study spots Protein was extracted and labeled with CyDye 2D-Image Data-Mining Protein spots were identified High-speed/-throughput 1D-RP mLC/NSI-MS/MS Analysis Mass SpectrometrySurgical Specimen

Back Ground (GISTs) 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. 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.

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

Cluster Analysis 43 spots (p < 0.01) Poor-prognosis GISTs Good-prognosis GISTs Pfetin 1513 spots 43 spots Wilcoxon test 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)

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

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

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

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

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

Multivariate Analysis of Metastasis Free Survival by Cox Regression

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