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Distinct Gene Expression–Defined Classes of Gastrointestinal Stromal Tumor

Umio Yamaguchi, Robert Nakayama, Kazufumi Honda, Hitoshi Ichikawa, Tadashi Hasegawa, Miki Shitashige, Masaya Ono, Ayako Shoji, Tomohiro Sakuma, Hideya Kuwabara, Yasuhiro Shimada, Mitsuru Sasako, Tadakazu Shimoda, Akira Kawai, Setsuo Hirohashi, Tesshi Yamada

From the Chemotherapy Division and Cancer Proteomics Project; Cancer Transcriptome Project, National Cancer Center Research Institute; Orthopaedic Surgery, Gastrointestinal Oncology, Gastric Surgery, and Clinical Laboratory Divisions, National Cancer Center Hospital; BioBusiness Group, Mitsui Knowledge Industry, Tokyo; and the Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

Corresponding author: Tesshi Yamada, MD, PhD, Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; e-mail: tyamada{at}gan2.res.ncc.go.jp

Purpose The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood.

Patients and Methods The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.

Results Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P < .05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P < .00001).

Conclusion CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.

Supported by the Program for Promotion of Fundamental Studies in Health Sciences, conducted by the National Institute of Biomedical Innovation of Japan, the Third-Term Comprehensive Control Research for Cancer, conducted by the Ministry of Health, the Labor and Welfare of Japan and the Ministry of Education, Culture, Sports, Science and Technology of Japan, and generous grants from the Naito Foundation and the Princess Takamatsu Cancer Research Fund. U.Y. is an awardee of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Tokyo, Japan). These fund resources played no role in designing and interpreting the results of this study.

Microarray data of this study have been submitted to the GEO (Gene Expression Omnibus) database (accession number GSE8167).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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