Yoshiyuki Suehara, Tadashi Kondo, Kunihiko Seki, Tatsuhiro Shibata, Kiyonaga Fujii, Masahiro Gotoh, Tadashi Hasegawa, Yasuhiro Shimada, Mitsuru Sasako, Tadakazu Shimoda, Hisashi Kurosawa, Yasuo Beppu, Akira Kawai, Setsuo Hirohashi

Abstract

Purpose

We aimed to develop prognostic biomarkers for gastrointestinal stromal tumors (GISTs) employing a proteomic approach.

Design

We examined the proteomic profile of GISTs using two-dimensional difference gel electrophoresis (2D-DIGE). The prognostic performance of biomarker candidates was examined using a large-scale sample set and specific antibodies.

Results

We identified 43 protein spots whose intensity was statistically different between GISTs with good and poor prognosis. Mass spectrometric protein identification demonstrated that the 43 spots corresponded to 25 distinct gene products. Eight of the 43 spots derived from pfetin, a potassium channel protein, and four of the eight pfetin spots had a high discriminative power between the two groups. Western blotting and real-time PCR showed that pfetin expression and tumor metastasis were inversely related. The prognostic performance of pfetin was also examined by immunohistochemistry on 210 GIST cases. The 5-year metastasis-free survival rate was 93.9% and 36.2% for patients with pfetin positive and negative tumors respectively (p<0.0001). Uni- and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinicopathological parameters examined, including risk classification and c-kit or PDGFRA mutation status.

Conclusion

These results establish pfetin as a powerful prognostic marker for GISTs, and may provide novel therapeutic strategies to prevent metastasis of GIST.

関連論文

1. Yoshiyuki Suehara, Tadashi Kondo, Kunihiko Seki, Tatsuhiro Shibata, Kiyonaga Fujii, Masahiro Gotoh, Tadashi Hasegawa, Yasuhiro Shimada, Mitsuru Sasako, Tadakazu Shimoda, Hisashi Kurosawa, Yasuo Beppu, Akira Kawai and Setsuo Hirohashi. Pfetin as a prognostic biomarker of gastrointestinal stromal tumors revealed by proteomics. Clin Cancer Res, 14, 1707-1717, 2008. [PubMed]（外部リンク）
2. Kikuta K, Gotoh M, Kanda T, Tochigi N, Shimoda T, Hasegawa T, Katai H, Shimada Y, Suehara Y, Kawai A, Hirohashi S, Kondo T. Pfetin as a prognostic biomarker in gastrointestinal stromal tumor: novel monoclonal antibody and external validation study in multiple clinical facilities. Jpn J Clin Oncol. 2010;40(1):60-72.[PubMed]（外部リンク）
3. Daisuke Kubota, Hajime Orita, Akihiko Yoshida, Masahiro Gotoh, Tatsuo Kanda, Hiroshi Tsuda, Tadashi Hasegawa, Yasuhiro Shimada, Hiroshi Kata, Kazuo Kaneko, Akira Kawai, Tadashi Kondo. Pretin as a prognostic biomarker for gastrointestinal stromal tumor: validation study in multiple clinical facilities. Jpn J Clin Oncol, in press